Course 3 Flashcards
How are cell functions regulated?
- Endogenous mechanisms ʹ source of regulatory signal is inside the regulated cell
o Hayflick limit, DNA damage control (-> p53 activation) - Exogenous mechanisms ʹ source of regulatory signal is outside the regulated cell
o Intercellular communication mediated by signalling molecules
o Interaction cell – extracellular matrix ʹ focal adhesion
o Interaction cell - cell - intercellular communication
What are focal adhesions?
Focal adhesions are cellular connections, anchor cells to extracellular matrix
o Intracellular actin filaments bound to proteins of extracellular matrix via
integrins
What is “anchorage dependence” ?
ʹ dependence of cell proliferation and survival on cell binding to extracellular matrix
o once cell loses contact with ECM, it undergoes apoptosis
o signal concerning the binding is mediated by integrins of focal adhesions
o cells have to bind to ECM and spread, to realize their proliferation
o mechanism of signalling - integrins (associated protein: talin) -> FAK (focal
adhesion kinase) -> Src kinase
What is direct intercellular communication?
= cells are in physical contact
o gap junction ʹ connection of cytoplasms
o interaction of plasma membrane molecules ʹ one cell gives of molecules on its cytoplasmic membrane, other cell notices the molecules via receptors on its cytoplasmic membrane
What is mediated intercellular communication?
cells are not in physical contact
o signalling mediated by signalling molecules ʹ one cell creates a signalling molecules and sends it out into the extracellular matrix, another cell located further away catches this signal molecule
What are gap junctions?
communicating cell junction (cell-cell)
o channel connecting cytoplasms of neighboring cells
o through the help of proteins connexins forming connexons
o 6 connexins form one connexon; two connexons of two cells connect and from
a gap junction
o opening and closing is mediated via so called tilting = connexins turn towards
each other (cause by Ca2+ ions)
- mechanism of signalling ʹ passage of ions and small molecules up to 1000 Da
o regulated passage through the channel
What is signalling mediated by the interaction of plasma membrane molecules like?
interaction of signalling molecule (ligand) bound to the plasma membrane of signalling cell with a receptor bound to the plasma membrane of target cell
Where can we find signaling via plasma membrane molecules?
in immune system - T lymphocytes can induce apoptosis to unwanted cells
o contact inhibition ʹ physical contact of cells stops proliferation (not in cancer cells)
o regulation of ontogenesis ʹ so called notch signalization ʹ way by which one cell
stops neighbouring cells differentiation to the same cell type
What is the chemical character of signaling molecules?
o proteins, peptides
o low molecular weight substances ʹ AA and their derivatives, nucleotides, steroids, retinoid, FA derivatives
o Gas molecules - NO, CO
endocrine signaling
through the bloodstream, over long distances
o endocrine gland and hormones
paracrine signaling
diffusion of signaling molecules into the surrounding connective tissue
o signal molecules from one cell to neighboring cells
o cytokines (local mediators)
autocrine signaling
basically a subtype of paracrine signalling, only difference is that the cell responds to the signaling molecule it produces itself
o cytokines
synaptic signaling
synapse in nerve cells
o neurotransmitters
How does a cell respond to a signal?
for a cell to receive a signal, it needs a receptor that will react to the
following signalling molecule
- different cells respond differently to the same signal
o e.g. acetylcholine increases heart rate in the heart but increases saliva secretion in the parotid gland
- Each cell is programmed to respond in a specific way to the specific combination of signals
- Cells are dependent on certain signal combinations ʹ e.g. they have certain
„surviving” signals, that they must receive constantly ʹ once the signal
stops working, the cell undergoes apoptosis
What is the structure and function of signaling molecules?
- Chemical character of signalling molecules: proteins and peptides, low molecular weight substances (organic compounds) and molecules of gases
- Function of signalling molecules ʹ mediated intercellular communication
o first messengers (extracellular signalling molecules) vs. second messengers (intracellular signalling molecules)
What are the main functional groups of signaling molecules?
- hormones ʹ regulation of metabolism and gene expression
- cytokines ʹ regulation of proliferation, differentiation and apoptosis
- neurotransmitters ʹ signal transfer within synapse
- retinoids ʹ regulation of embryonic development
o they are substances of vitamin A derivative (retinol) that is why it can be dangerous in pregnancy Æ overdose on vitamin A
What is the difference between hormones and cytokines?
- hormones ʹ endocrine signalling, small number of places of production, bigger variety of target cells, low variety of
effects
o hormones are usually produced in one place, but it affects a lot of cells - example insulin is synthesized only in the
pancreas, but effects all skeletal muscle - cytokine - paracrine/autocrine signalling, a lot of production sites, less variety of target cells, greater variety of effects
What are hormones?
Hormones - chemical character of hormones - proteins, peptides, AA derivatives, steroids
- group of hormones ʹ hypothalamus hormones, adenohypophysis, neurohypophysis, thyroid gland, calcium metabolism,
adrenal cortex, adrenal medulla, sex hormones and pancreatic hormones
What are the hormones of the hypothalamus?
- proteins and peptides
- includes mainly hormone that regulate the release of other hormones (mainly adenohypophysis hormones)
- somatostatin ʹ inhibits the release of somatotropin (growth hormone) from adenohypophysis
- somatoliberin ʹ antagonist of somatostatin, works against it
What are the hormones of adenohypophysis?
- proteins and peptides
- somatotropin (GH; growth hormone) ʹ regulates the expression of IGF-I
o itself does not induce growth but regulates the expression of the gene which does - prolactin (PRL) ʹ regulates lactation in mammals
- thyroid stimulating hormone (TSH; thyrotropin) ʹ regulates thyroid hormone release
- luteinizing hormone (LH) ʹ regulates the release of sex hormones from relevant tissues
o estradiol and progesterone from ovaries and testosterone from the testes - adrenocorticotropic hormone (ACTH) ʹ regulates the release of adrenal cortex hormones
What are the hormones of neurohypophysis?
- peptides
- vasopressin/antidiuretic hormone (ADH) ʹ stimulates water reabsorption in the kidneys
o synthesized in the hypothalamus and stored in neurohypophysis - oxytocin ʹ stimulates contraction of uterine muscles during labour (artificial
administration accelerates labour)
What are the thyroid hormones?
- derivatives of tyrosine
- thyroxin/Tetraiodothyronine (T4) ʹ regulates metabolism
- triiodothyronine (T3) ʹ regulation of metabolism is stronger than T4
What are the hormones of calcium metabolism?
regulate calcium and phosphate levels
- parathormone parathyroid hormone
- calcitriol derivative of vitamin D3, its synthesis begins in the liver and continues in the kidneys
- calcitonin thyroid peptide
What are the hormones of adrenal cortex?
- steroids: hydrophobic substances that are not trapped on the cell surfacepass through the plasma membrane of the cell directly into the cytoplasm where there are receptors waiting
- glucocorticoids - cortisol stimulates gluconeogenesis
- mineralocorticoids - aldosterone regulates sodium and potassium levels in blood
What are the hormones of adrenal medulla?
catecholamines, tyrosine derivatives
- adrenalin (epinephrine) mobilization of glucose and FA into the bloodstream (via β-adrenergic receptors) - fight-or-flight reaction
o ensures survival - fighting, fleeing, feeding and mating
- noradrenalin (norepinephrine) contraction of smooth muscles of the skin and intestinal tract (via α adrenergic receptors)
What are the sex hormones?
- steroids
- testosterone (testes) controls the male sexual differentiation and function of the male genital organs
- estradiol (ovaries) controls the female sexual differentiation and function of female genital organs
- progesterone (ovaries, placenta) maintain pregnancy
What are pancreatic hormones?
- proteins and peptides
- insulin regulates carbohydrate, lipid and protein metabolism lowers blood glucose
- glucagon insulin antagonist
What are cytokines?
- chemical character of cytokines - proteins
o groups of cytokines - a) growth factors, b) lymphokines and monokines, c) interferons and d) other cytokines
Growth factors
mainly regulation of cells of nonhemopoietic origin (everything except platelets and red blood cells and white blood cell)
TGF-B growth factor
TGF-β (transforming growth factor β produced in various types of cells (platelets)
o Inhibition and stimulation of proliferation of various types of cells
EGF growth factor
EGF (epidermal growth factor) produced in various types of cells (submandibular gland, macrophages)
o Stimulation of epithelial cell proliferation
FGF-1 growth factor
FGF-1 (fibroblast growth factor 1) produced in brain tissue
o Stimulation of proliferation of various types of cells (fibroblasts)
FGF-2 growth factor
FGF-2 (fibroblast growth factor 2) produced in nerve tissue
o Similar as to FGF-1 stimulates different type of cells
HGF- growth factor
HGF (hepatocyte growth factor) produced in cells of mesodermal origin (platelets, macrophages)
o Stimulation of hepatocyte proliferation
IGF-1 growth factor
IGF-I (insulin-like growth factor 1) liver is the main place of production
o Stimulation of proliferation of most cell types
o Very important can not live without it
IGF-II growth factor
IGF-II again main place of production is the liver
o Biological effects similar to IGF-I, however acts prenatally
NGF growth factor
NGF (nerve growth factor) - produced in various types of cells (smooth muscle cells, epithelial cells
o Sustaining of viability of embryonic neurons (works as a survival factor)
PDGF-growth factor
PDGF (platelet-derived growth factor) produced in plateletes
o Stimulates proliferation of dermal fibroblast
o Large role in wound healing thrombocytes release PDGF, which stimulaters fibroblast to proliferate and produce extracellular matter that clogs the wound in the skin
What are lymphokines and monokines?
Mainly regulation of cells of haemopoietic origin (platelets, red blood cells and white blood cells) , produced mainly in lymphocytes and monocytes
IL-1
IL-1 (interleukin 1) produced in activated macrophages
o Mediating of immune response and inflammatory response (inflammation = high level of IL-1)
IL-2
IL-2 produced mainly in activated T lymphocytes
o Stimulation of proliferation and differentiation of T cells
IL-3
- IL-3 produced mainly in T lymphocytes
o Stimulation of proliferation and differentiation of haemopoietic progenitor cells
IL-4
- IL-4 produced mainly in activated T lymphocytes
o Stimulation of proliferation and differentiation of B cells
IL-5
IL-5 produced mainly in T lymphocytes
o Stimulation of proliferation and differentiation of eosinophils (allergy)
GM-CSF
GM-CSF (granulocyte-macrophage colony stimulating factor) produced in various types of cells (macrophages), o stimulation of proliferation of various types of haemopoietic cells
What are interferons?
- antiviral activity and inhibition of cell proliferation
- INF-α (interferon alfa produced in leukocytes
o Antiviral effects and inhibition of proliferation of various types of cells and also immunomodulatory activity - INF-β produced in fibroblasts
o Biological effects similar like IFN-α - INF-γ produced in T cells
o Antiviral effects and inhibition of tumor cell proliferation and also immunomodulatory activity
o Belongs to a different family than INF-α and INF-β
What are the other cytokines?
- erythropoietin (EPO) ʹ produced in kidneys
o stimulation of proliferation and differentiation of erythroid progenitor cells (ensures the development of erythrocytes)
o during hypoxia increases the production of EPO production and thus increases the amount of red blood cells - TNF-α (tumour necrosis factor α; cachectic) ʹ produced in macrophages
o Induction of cell death (tumour cells
o Causes cachexia (weakness , congestion) in the final stages of cancer ʹ killing all cells - TNF-β (lymphotoxin) ʹ produced in lymphocytes
o Biological effects similar to TNF-α - growth hormones (GH) ʹ has some characteristics to cytokines, including recepotrs
What are neurotransmitters?
- chemical character of neurotransmitters: amino acids, amines etc.
- acetylcholine ʹ choline derivative, direct interaction with ion channels (ligand ʹ gated ion channels)
- GABA (γ-aminobutyric acid) ʹ biogenic amine, glutamate derivative, direct interaction with
ion channels
-
dopamine ʹ tyrosine derivatives, belongs to catecholamine family, interaction with
receptors associated with G proteins - serotonin ʹ tryptophan derivative, interaction with receptors associated with G proteins
What are retinoids?
- chemical character of retinoids - vitamin A (retinol)
- retinoic acid ʹ retinol derivative, regulation of embryonic development (morphogen)
What is the importance of cholesterol for the human body?
- cholesterol is in cell membranes it stabilizes membrane and lower its fluidity
o forms around 1/4 of all lipids in membranes
- has an amphipathic character (both polar and nonpolar)
- is a precursor to many significant derivatives
o bile acids ʹ die to their amphipathic nature, they can interact with both water and food in the intestine
their effect increases the surface area of fatty food, thus increasing the effect of enzyme decomposition
o substances with signaling function – steroid hormones, vitamin D
What are the 5 main classes of steroid hormones?
5 main classes
o gestagens - progesterone (necessary to maintain pregnancy)
o androgens - testosterone (anabolic hormone, that supports secondary sexual characteristics of men)
o estrogens - estriol, estradiol (supports secondary sexual characteristics of women)
o glucocorticoids - cortisol (affects energy metabolism)
o mineralocorticoids - aldosterone (increases the absorption of water and sodium from urine and excretion of potassium and H+ into the urine in the distal renal tubule = affects blood volume, blood pH, and plasma sodium
concentration)
- gestagens, estrogens and androgens are sometimes collectively referred to as sex hormones
What is vitamin D?
- its active form is calcitriol
- is not a true steroid, but has a similar mechanism of action ʹ intracellular
receptor binding and gene expression regulation - Although vitamin D can be produced from cholesterol after sun exposure,
it is considered to be a vitamin and therefore essential in our diet - Affects the body’s management of calcium and phosphates in the body
in medicine it is used to prevent bone diseases - Its precursor 7-dehydrocholesterol -> sunlight cleaves one of its rings ->
precalciferol -> cholecalciferol (inactive vitamin D3) -> hydroxylation in liver
and in the kidney leaving us with calcitriol
Where does cholesterol synthesis take place?
Most of it takes place in the cytosol and some in ER- but not always must cholesterol be produced, individual synthesis intermediates are used for the production o other substances, e.g. ubiquinone or vitamin D
What are the 3 steps of cholesterol synthesis?
o 1. Synthesis of isopentenyl diphosphate -
active isoprene unit (5C) - from Acetyl-CoA
a large part of this phase proceeds in
the same way as ketone synthesis
o 2. condensation of 6 isopentenyl diphosphates into one linear molecule - squalene (30C)
o 3. cyclization linear squalene undergoes a
series of reactions to a tetracyclic product -
cholesterol (27C)
Synthesis of isopentenyl diphosphate
- takes place in cytosol
- substrate - Acetyl-CoA
- intermediates - HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) and mevalonate
- HGM-CoA reductase ʹ key regulatory enzyme for cholesterol synthesis that reduces HGM-CoA to mevalonate
β-ketothiolase
Cholesterol synthesis
- Reverses the last β-oxidation
- 2 acetyl-CoA -> acetoacetyl-CoA
HMG-CoA synthase
Cholesterol synthesis
– adds a new 2C from Acetyl-CoA to acetoacetyl-CoA
HMG-CoA reductase
- cholesterol synthesis
- HMG-CoA reductase converts HMG-CoA to mevalonate
- It is a double reduction
o carboxyl group -> primary alcohol group - as a reducing agent we use 2x NADPH + H+
Condensation 2nd step in cholesterol synthesis
o 3x isopentenyl diphosphate (5C) Æ
farnesyl diphosphate (15C)
head = phosphate groups,
tail = carbon chain
condensation occurs between head and tail
o 2x farnesyl diphosphate (15C) ->
squalene (30C, linear molecules)
head-to-head interaction
Cyclization 3rd step of cholesterol synthesis
- long process, just know lanosterol ʹ 30 C intermediate, which already has 4 sterane rings
How is cholesterol synthesis regulated?
- an adult produces around 800mg of cholesterol in the liver and intestines daily
o from food- 300-400 mg (in total we should get about 1,1 g cholesterol) - cellular cholesterol levels in the cell regulate HMG- CoA reductase synthesis
- factors affecting HMG-CoA reductase
1) reductase transcription rate ʹ transcription factor = sterol regulatory element binding protein (SREBP)
low cholesterol activates SREBP, high inhibits it
2) reductase translation arte ʹ inhibited by non-steroidal metabolites derived from mevalonate
3) degradation of reductase ʹ high cholesterol concentration accelerates degradation of reductase
4) reductase activity - AMP-activated protein kinase (AMPK) phosphorylates reductase and thus decreases its activity, insulin dephosphorylates reductase, thereby increasing its activity, thereby promoting cholesterol synthesis
anti-cholesterol drugs target HMG ʹ CoA reductase and are called statins ʹ e.g simvastatin or lovastatin.
How are lipids transported in plasma?
metabolism of lipoproteins - lipoproteins and proteins ʹ high molecular components of blood plasma ʹ are used for transport of lipids in plasma
- ketone bodies travel freely dissolved in plasma,
fatty acids are already more complex
o short chain FA (up to 12C) are freely dissolved in plasma
o long chain FA must be bound to protein albumin
- other lipids are distributed in the body by lipoproteins
- lipoproteins are spherical particles of amphipathic nature
o have hydrophobic core) TAG and cholesterol ester) and a cover of amphiphilic molecules (apoporteins, phospholipids and cholesterol)
What are apoproteins?
- are found on the surface of lipoproteins
- act as membrane stabilizers, ligands for target tissue receptors and as cofactors of lipoprotein metabolism enzymes
- one apoprotein may have more than one role
o structural support - Apo B100 and Apo B48
o cofactors (activators) enzymes - Apo C-II (enzyme LPL) a APO A-I (enzyme LCAT)
o receptor ligands - Apo B100 (LDL-receptor), Apo E (scavenger receptor), Apo A-I (HDL receptor)
What are chylomicrons?
lipoproteins which transfer TAF and cholesterol from the intestine to the tissues ( to the place of consumption or storage)
VLDL (Very Low Density Lipoproteins)
transport of TAG from liver to tissues
IDL (Intermediary DL)
arise from VLDL after removal of lipid
LDL (Low DL)
transports cholesterol from the liver to the tissues
this lipoprotein carries cholesterol
throughout the body, contributing to
atherosclerosis
HDL (High DL)
transports cholesterol from
tissues to the liver, where the liver processes
them into bile acids
this lipoprotein deprives the blood
vessels of cholesterol and its high
blood level is considered as a positive
sign reducing the likelihood of
atherosclerosis ( = heart attack, stroke)
proteins have higher densitiy than lipids Æ higher
density lipoproteins have higher % prtoeins
What are chylomicrons?
- are formed in intestinal enterocytes and serve to transport TAG and CE ( cholesterol esters) from the intestine to the tissues
- they travel from the intestine first through the lymphatic pathways and through the ductus thoracicus and into the blood
- they obtain Apo E a Apo C-II in the blood from HDL
o Apo C-II activates lipoprotein lipase (LPL), which catalyzes the hydrolysis of TAG to FA and MAG
o MFA then penetrate into tissue - Chylomicrons gradually produce chylomicrons residues, which are smaller and contain a larger proportion of CE and
MAG - These residues are gradually taken up and removed by the liver (the receptor ligand is Apo E )
- In addition to Apo E a Apo C-II, chylomicrons have Apo B48 on their surface
VLDL
- Forms in the liver and serves to transport Tag from liver to the periphery
- Endothelial cells carry LPL (mainly in adipose and muscle tissues), which in peripherals begin to break down Tag inside
VLDL into FA and MAG (similar to chylomicrons) Æ VLDL is thus reduced to IDL
- CETP (cholesterol ester transport protein) – ensures the exchange between HDL to VLDL
o CE is transferred from HDL to VLDL
o Tag is transferred form VLDL to HDL
o This mechanism helps to efficiently transport lipids across the body
IDL
- Rise from VLDL by endothelial LPL activities
- They differ from VLDL in higher CE content and lower TAG content
- Circulation of IDL through the blood is terminated in the liver where they are:
a) absorbed and degraded
b) HRHL (heparin releasing hepatic lipase) cleaves TAG from IDFL and gets converted to LDL protein
LDL
- Most of these are derived from HRHL’s activities, the rest is synthesized de novo
- In their core they contain mainly CE, which they transport into tissues
- LDL is referred to as ͞bad͟ cholesterol because its acts as atherogenic
- At low cholesterol, body cells express the LDL ʹ receptor (for Apo B100 and Apo E) and trap LDL particles
- Plasma concentration should be below 3,0 mM, in diabetics below 2,5 mM
HDL
Their main role is to transport cholesterol from peripheral tissues to the liver where it can be converted to bile acids and excreted with the feces outside the body
- HDL particles are synthesized in the form of flat empty disks (like an empty balloon) in the liver and enterocytes
o After synthesis only have Apo AI, AII and AIII and a small amount of Apo C-II and Apo E on its membrane
o these blank disks are referred to as nascent ;just emerging or ͞coming to existenceͿ HDL
- action of the enzyme LCAT (lecithin cholesterol acyltransferase, cofactor Apo A-I), which esterified cholesterol when
transferred to HDL, nascent HDL gradually fills with cholesterol esters and is converted to HDL3 and HDL2α
o the difference between HDL3 and HDLϮα is the cholesterol conetnt - HDL3 has less cholesterol
- CETP activity brings TAG into both types of HDL
o HDL2α will become HDL2β after the addition of Tag, which travels to the liver where it is treated in the same
way as IDL
o Part of HDL2β disappears in the liver ( and its cholesterols are excreted in the faeces) and part is processed by
the enzyme HRHL
o If HRHL hydrolyses TAG inside HRHL HDLϮβ͕ then HDLϮβ becomes HDL3 and goes back into blood
- HDL is referred to as ͞good͟ cholesterol because it counteracts atherogenesis
- Its plasma concentration should be higher than 1.0mM in men and higher than 1,2mM in women
- Note: before menopauses women are protected from atherosclerosis by female sex hormones
Familial hypercholesterolemia
- Mutation of gene for LDL receptor
- Result - bad capture of LDL particles Æ increases levels of cholesterol in blood
- Excess cholesterol gets stored in the walls of vessels and causes the development of atherosclerosis and then further
complication (myocardial infarction or stroke) at a young age
Apo B-100
Apo C-II
Ligand for LDL receptor
Activator of LPL
What are the 3 main signaling systems?
o nerve ʹ uses neurotransmitters, a short signal distance
o endocrine ʹ uses hormones, long distance signal
o immune ʹ uses cytokines, acts in the close vicinity
- individual systems are very closely interconnected, no system can be said to be superior or inferior
o they work together through individual signaling molecules ʹ some molecules fall into multiple systems
example adrenalin = neurotransmitter and hormone
- signalling molecules have different effect on adult human and different on growing fetus in uterus (e.g. retinoids ʹ derivatives of Vit.A)
How is signaling divided?
signalling can be divided according to: distance signal travels; receptor location; specificity
- autocrine ʹ cell influences itself by feedback
- juxtacrine ʹ cell has signalling molecule integrated on its surface and influences the target cells by direct contact
- paracrine ʹcell produces a signal to the extracellular matrix and thus affects neighbouring cells
- endocrine ʹ cell produces a signalling molecules which goes to the blood by which the signal is transmitted to the target
cells - neurocrine ʹ signalling molecule reached the target cell via an axon
- pheromone ʹ it has not been directly demonstrated that it works in humans
What is autocrine signaling?
- serves to control the production of signalling molecules ʹ a certain concentration of signalling molecules stops their
further production - negative feedback ʹ control of signalling molecules production (e.g. growth hormones)
o concentration-dependent ʹ up to a certain concentration leads to receptor binding and cell response - positive regulation is quite rare in human͛s cell except for tumour cells ʹ they are positively regulated and therefore
multiply
Juxtacrine signaling
- the signal molecule is membrane-bound ʹ two cell contact is required (= signaling by touch)
- occurrence
o Notch signaling during the development ʹ cells prevents the differentiation of surrounding cells
In this way, neurons prevent neighboring stem cells from differentiating into other neurons
o In the immune system ʹ e.g. In the induction of apoptosis (FAS a FAS ligand)
o nexs ʹ channel in cell membranes connecting their cytoplasms
Paracrine signalling
- cells produce signalling molecules that affect cells in their close vicinity
o signalling molecule travels through tissue fluid - occurrence
o interaction of neighbouring cells ʹ e.g. during development (growth factors, morphogens)
o immune system ʹ uses special signalling molecules, called cytokines
o synchronization of GIT function ʹ the so called diffuse neuroendocrine system (DNES) ʹ more about this later .
Endocrine signaling
- hormones (products of endocrine glands) are excreted into blood or tissue fluid
o affect organs and tissues that are distance from their place of production
o kidney, adrenal gland, thyroid, parathyroid, testes, ovary, placenta
Neurocrine signaling
Neurocrine signaling
- is used in neuronal communication in nerve tissue
- neuron - body (soma, perikaryon) and processes (dendrites and axons)
o via axon the signal is in the form of an action potential
o myelin sheath allows the signal propagation ;signal ͞jumps͟Ϳ –> faster propagation
depolarization occurs only in nodes of Ranvier
- neuronal transport ʹ neurotransmitters come out of the end of the axon into the synaptic cleft
o in some cases, able to secrete hormones into blood
o combination of endocrine and neurocrine signalling - hypothalamic-pituitary system (statins and liberins)
oxytocin - effect smooth muscle, take part in milk secretion
vasopressin ʹ contraction of muscle in blood vessels, pressure increases, effects renal water resorption
What is a synapse?
- specific intercellular contact, which is always realized between the signaling cell axon and some other cell, which may be another neuron (information transfer), muscle cell (induce contract), glands (induce secretion)
o in the opposite direction, the neuron receives information about what is happening ʹ pain, injury
- consists of presynaptic membrane (with neurotransmitter), synaptic cleft, postsynaptic membrane (receptor)
- one nerve cell may have up to a thousand of synapses ʹ it is formed mainly in childhood (around 20 years of age, synapses are reduced, which are not used)
Neuronal transport
- neurotubules (microtubules) + kinesin + cargo (vesicles with neurotransmitter or hormone)
o microtubules are shorter than axons ʹ when the vesicle reaches the end of the microtubule, it falls down and must find a new path (microtubule) - Herring body - extension on axon, accumulation of vesicles with
hormone throughout an axon - Hypothalamic-pituitary system
o Divided into neurophysis (nerve tissue) and adenohypophysis (epithelium)
o Neurophysis ʹ non myelinated axons, glial cells (pituicytes), blood vessel
What are the functions of hormones?
o Affect the rate at which substances are released from a cell or enter the cell
o Stimulate the synthesis of proteins or other substances
o Activate or supress the activity of already existing enzymes in the target cell
- Polypeptide hormones and catecholamines need a receptor on the membrane
- Steroids and thyroxine are free to cross the plasma membrane and therefore have a receptor in the cytoplasm
- Hormones play a role in maintaining all aspects of homeostasis and some of the (catecholamines) are excreted in the
nervous system
Cells producing polypeptide hormones
- Have a light cytoplasm, a large light nucleus (light because the DNA is in euchromatin form), cristae mitochondria, RER, GA and contain secretory granules full of hormones on the basal side of the cell (close to capillaries which they are in contact with)
- Examples of such cells are those that are part of islet of Langerhans
o demonstration - immunohistochemistry (using marked antibodies)
o among cells is paracrine regulation via somatostatin
D cells - somatostatin ʹ supress the secretion of other hormones of islets of Langerhans (insulin and glucagon) and secretion of digestive enzymes in exocrine pancreas and GIT
- insulin ʹ insulin secretion is stimulated in B cells by glucose entering the cell into cell
o synthesis - nucleus -> mRNA -> GER -> preproinsulin (signalling sequence + c peptide) -> proinsulin (c peptide) ->
insulin
o transporter GLUT 2 allows the secretion of insulin from cell
o effect of insulin of the periphery ʹ binding on insulin onto its receptor which activates the receptor and causes
translocation
GLUT 4 transporters come from the GA to membrane, allowing glucose to enter the cell
Catecholamine producing cells
- adrenal medulla ʹ cells arranged in trabeculae
- DNES (diffuse neuroendocrine system) ʹ produces serotonin
Steroid hormone-producing cells
- Contain SER, tubular MIT and lipid droplets
- Adrenal cortex ʹ cells again form trabeculae
- hormones ʹ glucocorticoids, mineralocorticoids and sex hormones
o ovarium ʹ sex hormones are synthesized In follicles, theca interna cells and yellow body
o testes ʹ testosterone is produced by Leydig cells
Interaction of nervous and endocrine systems
- retina ʹ reacts to light ʹ cardiac clock ʹ cyclic changes in gene expression
o affects the production of melatonin in the pineal gland, GnRH, FSH, LH, estrogens and progesterone
What are ovarian follicles influenced by?
- Influenced by FSH ʹ its binding to the receptor in the primary and secondary follicles initiates the synthesis of estrogen
(estradiol) - progesterone is synthesized as an estrogen precursor
Thyroid hormones
- thyroglobulin and enzymes are synthesized in RER and GA and subsequently secreted into the lumen of follicles
- iodine pump pumps iodide from blood to colloid 9actve transport)
- colloid activates iodine and iodine binds to thyroglobulin = a storage form of thyroid hormones is formed a so called: iodothyroglobulin
- after signal binding (TSH) iodothyroglobulin is phagocytosed and in the lysosome is cut into the final hormone, which is
subsequently released into blood
How are steroid signaling molecules formed and degraded?
Steroid hormones:
Gestagens (progesterone), androgens (testosterone), estrogens (estradiol), glucocorticoids (cortisol) and mineralocorticoids (aldosterone)
- Steroid signaling molecules are synthesized from cholesterol
o The initial and final phases of their synthesis take place in SER, the rest in the matrix of mitochondria
o Formed for example in the adrenal gland and gonads - They are synthesized when stimulated by something ʹ the cells do not produce ready-made steroids
- Are hydrophobic ʹ in plasma they bind to transport proteins such as SHBG, CBG or albumin
- Steroid hormones pass freely through the cytoplasmic membrane and receptors are located in the cytoplasmic membrane
o Thyroid hormones have receptors inside the nucleus
o Hormone receptor complex binds to DNA and initiates transcription
Synthesis of steroid hormones
- Substrate - cholesterol
o Two sources - plasma (LDL particles, larger part) and sympathize de novo (smaller part) - transfer of cholesterol from the blood to cell is ensured by the LDL receptor
- transfer of cholesterol from cytoplasm to MIT is an ACTH-dependent steroidogenic acute regulatory proteins, which is also a regulatory step of the whole synthesis
- cholesterol (27C) -> pregnenolone (21C) -> progestagens (21C) in MIT matrix
o this is ensured by cytochrome P450 side chain cleavage
enzyme (P450scc) - cleaves side chain - from progestogens, the synthesis of different hormones begins to
proceed differently
1) glucocorticoids (21C)
2) mineralocorticoids (21C)
3) androgens (19C) –> estrogens (18C)
Formation of 21C steroid hormones
- most of the enzymes in these reactions are hydroxylases
- progesterone ʹ directly from
pregnenolone (it is only dehydrogenation on the 3rd carbon) - cortisol ʹ from progesterone by
triple hydroxylation to C11, C17 and C21
o enzymes - hydroxylases
o oxygen and NADPH are needed - aldosterone ʹ from progesterone
by double hydroxylation on C11
and C21 and subsequent oxidation
on C18
o enzymes- hydroxylases
aldosterone synthase
Production of 19C steroid hormones
- testosterone ʹ from progesterone, when shortened by 2C and keto group is formed on C17, which is subsequently reduced
- estradiol ʹ is formed directly from testosterone by the enzyme aromatase, which cleaves one carbon and gives the first
ring aromatic character
What are the different types of estrogens?
there are three estrogens
- estradiol = before menopause,
estriol= in pregnancy,
estrone = after menopause
o estradiol ʹ main estrogen that ensure changes during puberty and serves to maintain a sex life
o estriol ʹ produced mainly by the placenta (its decrease is a sign of fetal developmental disorder)
o estrone ʹ arises in peripheral tissues by conversion of androstenedione, which is produced in the adrenal glands
;in menopause there is a decrease in ovarian function͕ so that it is ͞replaced͟ by the adrenal glandsͿ
How is steroid hormone synthesis regulated?
1) release of cholesterol from internalized LDL
2) StAR protein ʹ cholesterol transporter through the inner MIT membrane
3) MIT side chain cleavage enzyme (depending on where it is, different hormones are produced: testes Ætestosterone, ..)
- signal ʹ pituitary hormones (ACTH, LH a FSH) or angiotensin II
How are steroid hormones degraded?
- steroid core can not be split!
- Steroids cannot be destroyed and are non-polar, so we cannot even get rid of them with urine ʹ That is why the liver had
to transform them
o We get rid of them similarly to xenobiotics = we change their structure to become polar substances, so they will not be retained in the body and excreted with urine - Small part is excreted unchanged in urine - UFC (urinary free cortisol)
Vitamin D
- Its active form is calcitriol
- It is not a true steroid but has a similar mechanism of action – intracellular
receptor and gene expression regulation - although vitamin D can be produced from cholesterol after sun expose, it is
considered a vitamin and therefore is essential in our diet - Affects the body’s calcium and phosphate levels ʹ in medicine it is used to
prevent bone diseases - Its precursor is 7-dehydrocholesterol -> sun light cleaves one of its rings -> precalciferol -> cholecalciferol (inactive vitamin D3) -> hydroxylation in liver and
kidney -> calcitriol
How is NO (nitric oxide) formed?
- Nitric oxide is cleaved from arginine with the participation of the enzyme NO synthase,
oxygen and NADPH - There are several types of NO synthases, each occurring in different tissues
o NO synthase I ʹ in neurons, where NO acts as a neurotransmitter
o NO synthase II ʹ in macrophages where NO helps kill bacteria
o NO synthase III ʹ in the endothelium, where NO participates in the regulation of
blood pressure ( it can expand blood vessels and thus reduce pressure)
Thyroid hormone production
- Synthesis requires trace element ʹ iodine
o Iodine deficiency in childhood = hypothyroidism (thyroid hormone deficiency)
o Iodine deficiency in childhood = cretinism
o Iodine is abundant in the sea, but there is very little in soil ʹ so it is now artificially
added into table salt to prevent hypothyroidism and cretinism
- Synthesis takes place on a large precursor molecule – thyroglobulin
- hormones are stored in the extracellular reservoir (colloid)
- in peripheral tissues, T4 is often converted to T3 because T3 is much stronger
Steps of thyroid hormone synthesis
1) synthesis of thyroglobulin into ER and GA and its subsequent excretion into the colloid
2) synthesis of enzymes and their transfer to colloid
3) secondary active iodide transport to the cell and then to the colloid
4) oxidation of iodides and iodination of tyrosine residues of thyroglobulin
5) joining of iodinated tyrosine residues in thyroglobulin Æ hormone formation
6) endocytosis and decomposition of thyroglobulin in lysosomes
7) releasing T3 and T4 into blood
o if there is insufficient iodine in diet, T3 will be more likely to occur, while as during high levels T4 will be more likely to occur.
Deiodanation and transport of hormones in blood
Deiodase removes I ʹ from inactive MIT and DIT, thereby recycling them
- Transport proteins in blood - TBG (thyroxine-binding globulin), albumin
- Peripheral deiodinase in target tissues selectively removes iodine from position 5’ to T4, resulting in more effective T3
o T4 is essentially a prohormone with intrinsic activity
- Thyroid disorders are the most common endocrine disease, far more common than diabetes for example
o Hypothyroidism – metabolism slows down = patients get colder, they will want heat, they can gain weight
o hyperthyroidism ʹ metabolism speeds up = body temperature increases, loses weight
Peptide hormones
- peptide hormones are hydrophilic and thus freely soluble in plasma
- affects cells by binding to the receptor on their surface ʹ after binding activates the membrane enzyme or G protein
- neurotransmitters and neuromodulators - neuropeptides, opioids,
- hypothalamic releasing hormones and pituitary peptides - somatoliberin, somatostatin, ACTH
- hormones of energy metabolism ʹ insulin and glucagon
- growth factors - IGF, CSF, EPO
- GIT hormones - gastrin
General peptide hormone synthesis steps
- Synthesis proceeds in the same way as any other peptide for export
1) hormone gene transcription -> 2) translation -> 3) transport to ER -> 4) signal sequence cleavage -> 5) posttranslational modification in GA and eventually cleavage
o proinsulin -> insulin
o POMC (proopiomelanocortin) -> beta-endorphin, MSH and ACTH - Finished hormones are most commonly stored in GA granules until a signal for their secretion is received
Mechanisms of peptide hormone release
- Constitutive secretion ʹ secretion is continuous and only a small amount is stored in secretory vesicles
o Plasma proteins, clotting factors - Regulated secretion ʹ secretion takes place only in response to signal and a certain amount of substances is stored in
the secretory vesicles in cell (secretion from cell is after signal Æ e.g via an increase in calcium ion levels in cell)
o Cytokines, neuropeptides,
How is a signal transferred across plasma membrane?
-diffusion of gas molecules
– Diffusion of hydrophobic molecules ʹ bind to intracellular receptor (e.g steroid hormones)
- Interaction of signalling molecule with membrane receptor
Diffusion of gas molecules
- Nitric oxide (NO) ʹ produced by the deamination of arginine (enzyme NO synthase)
o After its synthesis it travels from the cell directly into the target cell
o In target cells activate the appropriate enzyme (guanylate cyclase), which takes care of the rest
o Results in smooth muscle relaxation - Carbon monoxide (CO) ʹ works similarly to NO
How are hydrophobic molecules diffused?
Hydrophobic molecules like steroid hormones, thyroid hormones, retinoids, or vitamin D, can freely diffuse into cell through the plasma membrane ʹ thus they don͛t need a membrane receptor, only an intracellular receptor
- Mechanism of hydrophobic molecules is usually ʹ entry to cell— intracellular receptor
binding— hormone-receptor complex formation— binding to DNA— influencing DNA expression
Interaction with membrane receptor
Interaction with membrane receptor -> receptor produced intracellular signal
- Association constant - the higher it is, the better the signaling molecules bind to the receptor
- binding of signaling molecule to membrane receptor causes a conformational change in the receptor
What is the structure of membrane receptors?
- they are large proteins that cross through the cytoplasmic membrane
- have 3 parts (domains) ʹ extracellular, transmembrane and cytoplasmic
- have characteristic structural domains
o extracellular ʹ e.g. immunoglobulin-like domain
o intracellular ʹ e.g. protein kinase or death domain
receptor desensitization
ʹ as the word suggests ʹ it desensitizes the
receptor
o receptor stops reacting to a signal Æ the same concentration
causes a lower effect
o long lasting signal = lowers the receptor association constant
receptor down-regulation
ʹ degradation of receptors after signal
molecule binding
o after binding of the signal molecule, the receptor complex is internalized (receptor-mediated endocytosis), and the molecule
falls off the receptor and returns the receptor back to the plasma membrane
o signaling molecule travels to the lysosome where it is destroyed
o but some part of the receptor travels to the lysosome, along with the signaling molecule, where it is also destroyed
o long-lasting signal = lowers the number of receptors
What are the different types of membrane receptors?
- ion channel linked receptor ʹ ligand-gated ion channels
- G protein-linked receptors
- Protein kinase-linked receptors
- Death domain-linked receptors
- Receptors regulating proteolysis
Ion channel-linked receptor
- These receptors use synaptic and intracellular signaling (e.g. Ca2+ release from SER during muscle contraction)
- Causes a change in membrane potential, causing further changes in the cell
- The main type of receptors in nerve tissue
G protein-linked receptors
- Have a specific structure - have 7 transmembrane regions
- G protein - 3 subunits - α ;alfa͕ largest, carrying GDP or GTP), β ;beta and γ ;gamma
o function ʹ activation of enzyme after signal from receptor - example ʹ hormone receptor binding
-> receptor activation
-> G protein attachment
-> disconnection of GDP
-> GTP binding
-> detaching of G protein from receptor
-> disconnection of α; with GTP from β and γ
-> binding of α (with GTP) to the enzyme
-> enzyme activation - after some time, GTP becomes GDP ʹ at
that moment α binds the enzyme and
reconnects with β and γ
Protein kinase-linked receptors
- two types ʹ receptor kinases (with intrinsic kinase activity) and receptors associated with kinases
- receptors kinases ʹ intracellular domains of these receptors have kinase activity (they can phosphorylate)
o two types of receptor kinases
o receptor tyrosine kinases ʹ receptor for everything except TGF-β (e.g. EGF, insulin, IGF-I, NFG, PDGF…Ϳ
o receptor serine-threonine kinases - receptors for TGF-β - Protein kinase-associated receptors - individual kinases are attached to the intracellular domains of these receptors
o Two types of receptors associated with protein kinases
o Jak kinase and Src kinase
o examples of receptor ligands associated with protein kinases ʹ growth hormone, erythropoietin, interferons
Death domain-linked receptors
- the death domain is the intracellular part
o the final effect of their signalling pathways is apoptosis ʹ activation of the death domain receptor kills the cell - adapter proteins - e.g TRADD or FADD
- examples of ligands that bind to death domain receptors ʹFas ligand, TNF
- this type of signalling is used, for example by NK cells to kill tumour cells and virus-infected cell
Receptors regulating proteolysis
- the ligand binding receptor through the appropriate proteins regulates proteolysis of a particular protein by phosphorylation and subsequent ubiquitination
- examples of ligand regulating proteolysis - IL-1
What molecules mediate intracellular signaling?
- Molecules that diffuse into the cell ʹ like gas molecules and hydrophobic molecules
- Types of molecules mediating intracellular signaling after the interaction of extracellular signaling molecules with
receptor:
o Ions͕ small organic molecules;͞second messengers ͞Ϳ͕ GTP binding proteins, protein kinases, other proteins
Intracellular NO signaling
- After diffusion of NO into the smooth muscle cells, guanylate cyclase is activated
- Activated guanylate cyclase converts GTP to cGMP
- cGMP activates protein kinase G (PKG)
- PKG inhibits the actin-myosin -> vasodilatation
Intracellular signaling of hydrophobic molecules
- After diffusion of a hydrophobic signaling molecule, binds to the intracellular
receptor and forms a molecule-receptor complex - The molecule-receptor complex goes to the nucleus, where it binds to DNA and
directly affects transcription
Intracellular signaling mediated by ions
- Signalling via ligand-regulated ion channels
- Change of intracellular Na+
/K+ -> change of cell membrane potential
o Change of membrane potential in neurons is of special importance ʹ it can cause action potential (excitement)
- Change in cytosolic Ca2+ levels- as part of IP3/DAG signalling pathway
o After the release from ER through ion channels in the ER membrane
o Ca2+ pumps are responsible for maintaining low cytosolic Ca2+ levels
o Calmodulin ʹ protein that binds Ca2+
Second messengers
- small organic molecules that mediate intracellular signalling
o some textbooks treat all IC molecules as secondary messengers - are involved in signalling through receptors associated with the G protein
- types of second messengers
o inositol triphosphate (IP3)
o diacylglycerol (DAG)
o cyclic adenosine monophosphate (cAMP)
o cyclic guanosine monophosphate (cGMP) - G protein ʹ provides signal transmission from the receptor to the intracellular effecter molecule
o There is a stimulatory G protein (Gs) and an inhibitory G protein (Gi)
o signalling depends on the what effector molecules G protein activates
phospholipase C (PLC) ʹ breaks down the phospholipid PIP2 to IP3 and DAG
adenylate cyclase - converts ATP to cAMP
cGMP phosphodiesterase ʹ breaks the bond between phosphate and 3rd carbon in cGMP—GMP is formed
guanylate cyclase - converts GTP to cGMP
Intracellular signaling of GTP binding proteins
- GTP binding proteins have bound GTP (and are active) or GDP (and are inactive)
- GTP binding protein is G protein or Ras protein (which plays a role in signaling from receptor tyrosine kinases)
Intercellular signaling of protein kinases
- Protein kinases are enzymes that phosphorylate certain proteins
- E.g. tyrosine kinases and serine-threonine kinases
- Types of protein kinases in intracellular signalling
o Receptor-associated protein kinases
Src kinase and JAK kinase - STAT signalization
o Protein kinases of intracellular signalling cascades
Raf kinases and MAPKK - MAPK signalling cascade
PI3 kinase ʹ signalling from receptor tyrosine kinases
o Terminal protein kinases ʹ are at the end of the signalling cascade, they are already realizing the signal PKC, CAMK, PKA, MAPK, PKB;Akt and IKb kinase
Intracellular signaling mediated by other proteins
- They are mostly adapter proteins and enzymes with a different function than protein kinases
- Adapter proteins ʹ e.g Grb2 and Sos ʹ proteins associated with receptor tyrosine and receptors with death domains
- enzymes ʹ e.g. enzymes activated by G protein - PLC, adenylate cyclase, cGMP phosphodiesterase
o caspases activated through death domain receptors
Mechanisms of signal realization in the cell
- regulation of membrane potential – by ligand-regulated ion channels
- regulation of the expression of the respective proteins ʹ either by nuclear receptors or by activation of transcription
factors - regulation of the activity of respective proteins mostly regulation of the activity based on phosphorylation
Ligand-regulated ion channels
- can be opened by both extracellular ligands and intracellular
- their opening leads to the passage of ions, which changes the membrane potential and transforms the chemical signal into an electrical one
- application of ligand-regulated ion channels
o in synaptic signaling ʹ membrane depolarization is essential for neurons and conduction
o in photoreceptor signaling in rods ʹ in the darkness, there is a lot of cGMP in the cytoplasm in the retina cells that keeps certain ion channels permanently open
the effect of light on the cell activates opsin, which is a membrane receptor associated with the G protein
ʹ G protein activates cGMP phosphodiesterase, which immediately decomposes cGMP in the cytosol.
once cGMP levels fall, the ion channels are closed and cell hyperpolarization occurs
Nuclear receptors
- they are intracellular receptors of extracellular hydrophobic molecules
- function ʹ ligand binding to the receptor forms a complex that translocates to the nucleus and affects gene expression
- nuclear steroid hormone receptors are homodimers
Phosphorylation as the main mechanism of signal realization
- is realized by terminal protein kinases
- membrane-associated kinases are always tyrosine kinases
- kinases in the cytosol are always serine-threonine kinases
o only exception is the TGF-β ʹ receptor - this is a serine-threonine kinase in the membrane
Protein kinase G – PKG
- in NO signaling
- there is cGMP in cell -> PKG activation -> inhibition of actin-myosin complex -> relaxation of vascular smooth muscles—-
vasodilation
Protein kinase C - PKC
- in IP3/DAG signalling
- there is DAG and Ca2+ in the cell -> PKC activation-> phosphorylation of different proteins in different cell types
Calmodulin-dependent kinase - CAMK
- in Ca2+ signaling
- release of Ca2+ from ER -> binding to calmodulin Æ complex Ca2+-calmodulin activates CAMK -> phosphorylation of
transcription factors Æ regulation of expression of relevant genes
Protein kinase A - PKA
- in cAMP signaling
- there is cAMP in the cell -> PKA activation -> phosphorylation of transcription factors and other target proteins
- phosphorylates example glycogen phosphorylase (an enzyme of glycogenosis) and CREB (transcription factor)
MAP kinase - MAPK (Mitogen-Activated Protein Kinases)
- in Ras/MAPK signaling
- active MAPKK -> activation of MAPK -> phosphorylation of transcription factors Æ expression of relevant genes
Protein kinase B - PKB; Akt
- in PI3/Akt signalling
- active PI3 kinase -> PKB activation -> Bad protein phosphorylation -> Bad protein binding by 14-3-3 -> inhibition of
apoptosis - free Bad protein blocks the anti apoptotic protein, triggering apoptosis
Receptor serine-threonine kinase
- in Smad signaling
- ligand linked activation of dimer– activation of receptor cytoplasmic domain (phosphorylation) Æ phosphorylation of
Smad2/Smad3 -> oligomerization with Smad 4 (transcription factor) -> regulation of gene expression
JAK kinases
- in STAT signaling
- dimerization of receptor after ligand interaction— mutual phosphorylation and activation of JAK kinases—
phosphorylation and activation of cytoplasmic domains of receptor— binding and phosphorylation of STAT proteins—
dimerization of STAT proteins (transcription factor)– regulation of transcription of relevant genes
IκB kinase
- in NFκB signaling
- receptor oligomerization after ligand interaction– binding of other proteins— phosphorylation and activation of IkB
(inhibitor of kappa B) -> ubiquitination and subsequent degradation of IkB -> release of NFkB ;transcription factor) ->
regulation of gene expression
Kinase complex CK1, GSK3, axin and APC
- in WNT signaling
- receptor interaction (Frizzled) with ligand (Wnt = Wingless) -> activation of Dishevelled protein Æ binding and
activation of CK1, GSK3, axin, and APC complex Æ prevention of B-catenin phosphorylation (transcription factor) catenin
Æ stable ɴ-catenin -> regulation of gene expression
Cell signaling pathways
- Signalling pathways ʹ signal transmission from the primary signal (signalling molecule) to its realization in the cell
(physiological responses)
o Interconnection of signalling paths = signalling network - The same signalling molecule elicits different responses in different cell types
NO Signalling
- Nitric oxide (NO) is produced in the body by deamination from arginine (arginine—- citrulline + NO; by the enzyme NO-
synthase) - Signalling pathways - NO -> diffusion into smooth muscle cells around blood vessels -> activation of guanylate cyclase -
> production of cGMP -> PKG activation -> inhibition of actin-myosin -> muscle cell relaxation -> vasodilation - function ʹ regulation of vasodilation
- regulation
increases- nitroglycerin (provides more NO)
o lowers - cGMP phosphodiesterase inhibitors (viagra) - NO is also used in immunity ʹ activated macrophages synthesize NO in the fight against microorganisms
Signaling of hydrophobic molecules
- steroid hormones ʹ cortisol, aldosterone, testosterone, estradiol, progesterone
- thyroid hormones - thyroxine (T4)
- retinoids ʹ retinoid acid (vit. A)
- vitamin D - vitamin D3
- example of signaling ʹ stimulation of gluconeogenesis by cortisol
o cortisol -> diffusion to liver cells -> binding to intracellular receptor -> translocation of cortisol receptor complex to the nucleus –binding to the regulatory gene region of gluconeogenesis -> expression of genes -> gluconeogenesis
Adrenal cortex hormone signaling
o Glucocorticoids - cortisol stimulates gluconeogenesis
o mineralocorticoids ʹ aldosterone regulates ion levels
Sex hormone signaling
o testosterone ʹ stimulates spermatogenesis, ensures development of secondary sexual characteristics, promotes anabolism
o estradiol ʹ controls the menstrual cycle and ensures the development of secondary sexual characteristics
o progesterone ʹ helps implant the fertilized egg in the uterus
Thyroid hormone signaling
o Thyroxine (T4) and triiodothyronine (T3) ʹ metabolic regulation
Retinoid signaling
o Retinoic acid ʹ functions as a morphogen = signaling molecule used in fetal uterus development
Disbalances of morphogens leads to various congenital developmental defects
What is synaptic signaling?
- Signal transmission between two neurons or between a neuron and another target cell (e.g. muscle)
- It is mediated by neurotransmitters, which are amino acids, amines͕ and esters͙
o Neurotransmitters can be both excitatory and inhibitory
What are examples of neurotransmitters?
o acetylcholine ʹ choline derivative, a
neurotransmitter of the neuromuscular junction
o GABA - gamma-aminobutyric acid, glutamate derivative, major inhibitory NT in CNS
o dopamine ʹ tyrosine derivative, belongs to
catecholamines
o serotonin ʹ tryptophan derivate
- signaling examples ʹ signal transmission between two neurons by acetylcholine
o acetylcholine -> opening of Na+ /K+ channels in plasma membrane -> entry of Na+ into cell -> change in membrane potential (depolarization) Æ electrical signal
IP3/DAG signaling
- signaling through G protein ʹcoupled receptors
- activated phospholipase C (PLC) catalyzes the reaction of PIP2 -> IP3 + DAG
o PIP2 - phosphatidylinositol-4,5-bisphosphate
o IP3 – inositol triphosphate ʹ serves as a ligand for a ligand-regulated ion channel that releases Ca2+ from ER
o DAG - diacylglycerol ʹ activates protein kinase C (PKC)
What is Protein kinase C (PKC)?
- Ca2+ dependent serine-threonine kinase
o Realizes a signal based on phosphorylation of target proteins - Examples of signalling IP3/DAG ʹ stimulation of platelet aggregation by thrombin
o thrombin -> activation of membrane receptor– activation of G protein– activation of PLC -> degradation of
PIP2
DAG -> PKC activation
IP3 -> Ca2+ release from ER
o Ca2+ + active PKC = functional PKC -> protein phosphorylation— platelet granule release– aggregation
- Other PKC target proteins
o Membrane receptors ʹ desensitization of EGF receptor, activation of Ca2+ ATPase
o Signalling pathways kinases ʹ activation of Raf kinase (connection of Ras.MAPK signalling pathway ) - Other examples of IP3/DAG signalling pathways
o acetylcholine ʹ contraction of smooth muscle cells
o vasopressin ʹ glycogenolysis in hepatocytes
Ca2+ signaling
- Partially linked to IP3/DAG signalling (IP3 acts as a ligand for Ca2+ ion channels)
- After the release of Ca2+ from ER, calmodulin protein starts to take up free protein Ca2+ in the cytoplasm
o Calmodulin is a dimer and each of its subunits has 2 free spots for calcium, therefore, the whole calmodulin will receive 4
Ca2+ - Calcium-saturated calmodulin activates Ca2+-dependent kinase (CAMK)
- CAMK ʹ realizes signals based on the phosphorylation of target proteins
- Pathway examples - Ca2+ -> binding to calmodulin -> CAMK activation -> phosphorylation of CREB protein
(transcription factor) -> binding to the CRE region in the regulatory section of target genes– transcription— physiological response - Regulation of Ca2+ signaling - Ca2+ ionophores (ionophore is a substance enabling ion transfer through lipid barrier)
cAMP signaling
- Signalling from G protein ʹcoupled receptors– activation of adenylate
cyclase - Activated adenylate cyclase catalyses the reaction of ATP— cAMP
- cAMP ʹ activates protein kinase A (PKA), a serine-threonine kinase that realizes a signal based on the phosphorylation of target proteins
- cAMP phosphodiesterase ʹ catalyses the reaction of cAMP— AMP
- examples of cAMP signalling ʹ stimulation of glycogenolysis by glucagon in the liver
o glucagon -> membrane receptor activation -> G protein activation -> adenylate cyclase activation -> cAMP production -> PKA activation
-> glycogen phosphorylase activation —glycogenolysis - PKA target proteins
o Glycogen phosphorylase ʹ induction of glycogenolysis
o CREB protein - cAMP response element binding, transcription factor
binding to the CRE region in the regulatory section of genes
-
Other examples of cAMP signalling
o adrenalin ʹ an increase in the frequency of heart contractions
o TSH ʹ thyroxine secretion for the thyroid gland - Regulation of cAMP signalling ʹ cholera toxin, phosphodiesterase inhibitors
(caffeine)
Photoreceptor signaling
- Mechanism of converting a light signal into electrical in rods of the retina
- cGMP ʹ opens ligand-regulated ion channels in the membrane
o in the dark, there are many in the cell- channels are open = no hyperpolarization - photoreceptor signalling ʹ light radiation ʹ light radiation -> rhodopsin activation -> G protein activation-> cGMP
phosphodiesterase activation -> cGMP degradation -> ion channel closure -> membrane hyperpolarization -> electrical
signal
Ras/MAPK signaling
- signalling of most classical growth factors (except TGF-β via receptor tyrosine kinases)
o EGF, FGF-1, FGF-2, HGF, IGF-I, IGF-II, NGF, PDGF - Signalling example - EGF -> activation of membrane receptor -> activation of GRB2 and SOS -> activation of Ras -> activation of Raf -> activation of MAPKK -> activation of MAPK -> activation of transcription factors – proliferation
- The whole signalling is complicated because the molecules have other names
o Raf = MAPKKK, MEK = MAPKK, ERK = MAPK
o Raf is a non-receptor serine ʹthreonine kinase - Ras/MAPK function is mostly a regulation of proliferation in different cells
- Other examples of Ras/MAPK signalling
o insulin ʹ regulation of metabolism in many cell types
o EGF ʹ stimulation of proliferation in epithelial cells
o HGF ʹ stimulation of proliferation in hepatocytes - regulation of Ras/MAPK signalling ʹ since cells use this pathway to promote
proliferation, in pharmacology it is targeted to treat tumours (as an inhibitor)
- signalling of most classical growth factors (except TGF-βͿ via receptor
tyrosine kinases
o EGF, FGF-1, FGF-2, HGF, IGF-I, IGF-II, NGF, PDGF - Signalling example - EGF -> activation of membrane receptor -> activation
of membrane receptor Æ activation of GRB2 and SOS -> activation of Ras -
> activation of Raf -> activation of MAPKK -> activation of MAPK ->
activation of transcription factors Æ proliferation - The whole signalling is complicated because the molecules have other
names
o Raf = MAPKKK, MEK = MAPKK, ERK = MAPK
o Raf is a non-receptor serine ʹthreonine kinase - Ras/MAPK function is mostly a regulation of proliferation in different cells
- Other examples of Ras/MAPK signalling
o insulin ʹ regulation of metabolism in many cell types
o EGF ʹ stimulation of proliferation in epithelial cells
o HGF ʹ stimulation of proliferation in hepatocytes - regulation of Ras/MAPK signalling ʹ since cells use this pathway to promote
proliferation, in pharmacology it is targeted to treat tumours (as an
inhibitor)
What is SMAD signaling?
- TGF-β signalling via receptor serine-threonine kinase
- Example of signalling ʹ inhibition of
proliferation by TGF- β
o TGF- β
->activation of membrane receptor
-> activation of Smad2/Smad3 protein
-> oligomerization of Smad2/Smad3 a
Smad4 (transcription factor is formed)
-> oligomer binding to the regulatory
region of the p15 gene
-> transcription
-> p15 protein expression
-> inhibition of cell cycle progression
-> inhibition of proliferation - Smad signalling often inhibits proliferation in different cell types
- Smad signalling activated is regulated by TGF-β receptor inhibitors
What is STAT signaling?
- Signalling of most cytokines regulating cells of haemopoietic origin via receptors associated with Jak kinases
- Ligands of receptors associated with Jak kinases IL-2, IL-6, IFN-gamma, erythropoietin (EPO), growth hormone
- Example of signalling ʹ stimulation of erythrocyte proliferation and differentiation by erythropoietin
o Erythropoietin -> membrane receptor dimerization -> mutual activation (phosphorylation) Jak kinase ->
membrane receptor activation (phosphorylation)— phosphorylation and dimerization of STAT proteins (transcription factor formation)— binding to Bcl-xL gene region—transcription– protein Bcl-xL —apoptosis inhibition—proliferation and differentiation - Other examples of STAT signalling
o IFN-gamma - activation of macrophages
o growth hormone ʹ
stimulation of IGF-I in liver and other cells - STAT signalling is regulated
through Jak kinase inhibitors
o There is also a potential
use in the treatment of blood
cancer
Signaling of death domain receptors
- Death domain receptor ligands - Fas ligand, TNF (tumour necrosis factor)
- caspases ʹ proteins involved in the process of apoptosis
o activated by proteolytic cleavage - case of death domain receptor signalling ʹ induction of apoptosis of virus-infected cell
via Fas ligand anchored to the T cell membrane
o Fas ligand -> activation and trimerization of Fas receptors in the infected cell membrane— binding of procaspase 8 and FADD adapter protein (DISC complex formed) —activation of caspase 8—activation of caspase 3–proteolytic cleavage of death substrates—realization of apoptosis - Signalling via death domain receptors is used to induce apoptosis
o TNF ʹ induction of apoptosis in tumour cells - Regulated by specific caspase inhibitors
NFĸB signaling
- In response to damage and infection
- Ligand receptors for NFĸB signalling - IL-1, TNF-α
- Example of NFĸB signaling - IL-1 ʹ induction of inflammatory response based on the expression of inflammatory cytokines in
T lymphocytes
o IL1-1 -> membrane receptor activation -> activation of IĸB kinase -> phosphorylation of IĸB -> ubiquitination of IĸB -> degradation of IĸB -> release of NFĸB (transcription factor) from IĸB binding -> binding to DNA ->
transcription -> expression of inflammatory cytokines -> induction of inflammatory response - regulation of NFĸB signalling ʹ NFĸB inhibitors
Wnt signaling
- Wnt is a signalling molecule
- Membrane Wnt receptor = Frizzled
- Example of Wnt signalling ʹ regulation brain cell development
o Wnt -> activation of Frizzled -> activation of Dishevelled -> inactivation of CK1-GSK3-axin-APC -> prevention of β-catenin phosphorylation -> prevention of β-catenin ubiquitination -> prevention of β-catenin degradation ->binding of β-catenin to DNA -> transcription of relevant genes -> regulation of development
- β-catenin is a co-activator of the transcription factor
- Wnt signalling function ʹ regulation of ontogenesis, e.g brain
o Overexpression in tumour cells - Wnt signalling is regulated by inhibitors of individual members of the signalling pathway, which can potentially be used
in tumour therapy
Signaling via signals
endocrine ʹ hormones (= highly active substances that are produced by endocrine glands and then secreted into the blood,
and ultimately to the target cell/tissue/organ where they have a specific effect; they can work at very low concentrations (10-8 - 10-11M)
paracrine ʹ cytokines
autocrine ʹ cytokines
synaptic ʹ neurotransmitters
What are the endocrine glands?
- Epiphysis (Pineal gland)
- Hypophysis (Pituitary gland)
- Thyroid glands and parathyroid gland
- Thymus
- Adrenal glands
- Ovaries and Testes
- Pancreas
What makes up the diencephalon?
Thalamus, Hypothalamus, and Epithalamus
What is the thalamus?
o integrating centrum -> its main function is to transfer signals from the lower parts of the nervous system (spinal cord, brainstem, and cerebellum) and basal ganglia to the cortex and striatum
What is the hypothalamus?
o One of the few parts of the brain in which there is sexual dimorphism
o Has very complex functions—basically regulates all-important activities of the body
Circadian cycles (e.g sleep -> even longer periods, such as puberty), whose automation is found in the suprachiasmatic nucleus (large number of cells directly behind the eyes)
Hormone productionʹ> oxytocin, ADH, statins (somatostatin = GHIH, prolactin inhibiting hormone = dopamine = PIH) and liberins (GRGH, CRH, GnRH, TRH)
thermoregulation
centers regulating hunger and thirst
sexual behavior and probably sexual orientation
ͣfight-or-run ͞response
sense of pleasure
What is the epithalamus?
Posterior segment of the diencephalon. Contains the thalamus, hypothalamus, and pituitary gland
Pineal gland
hormone: melatonin
o chemical structure: amine
o typical effects: involved in biological rhythms (circadian rhythms)
o regulation by: light and dark cycles (maximum production at night)
Circadian rhythms:
o By Earth rotating around its axis, 24 hours a day/night cycles of light and darkness accompanied by the evolution of all life forms
o Biologicals cycles:
sleep ʹ waking
hormonal secretion
body temperature and blood pressure
motor activity
starvation ʹ fullness/satiation
Circadian rhythm disorders:
o sleep period disorders (genetically determined)
advanced sleep phase (19 ʹ 4 o͛clockͿ
delayed sleep phase (2 ʹ 11 o͛clock)
o Metabolic syndrome (obesity, diabetes mellitus)
o Blood pressure (hypotension, hypertension)
o Coronary syndrome (myocardial infarction)
Adenohypophysis (anterior pituitary -> ectodermal origin)
Growth Hormone GH
↑ growth + metabolism hypothalamic h.
Prolactin PRL
↑milk production +
secretion
hypothalamic h.
Thyroid-stimulating hormone
TSH ↑ thyroid gland hypothalamic h. + T4
Adrenocorticotropic hormone
ACTH ↑ adrenal cortex →
glucocorticoids
hypothalamic h. a
glucocorticoids
Follicle-stimulating hormone
FSH ↑ production of ova and sperm
hypothalamic h.
Luteinizing hormone LH ↑ ovaries and testes hypothalamic h.
Regulation of growth
insulin-like growth factor, IGF͟-> its production is stimulated by GH and may be limited by e.g. intensity of GH, lack of
GH receptors͙
there are generally 3 growth periods in humans:
o Infantine ʹ up to 2. Years of age (50 % of final height)
axis: glucose – insulin – IGF-I
o Children ʹ until the beginning of pubertal development (30 % of height)
axis: growth hormone– IGF-I
o Pubertal ʹ up to adult height (20 % of height)
axis: growth hormone– IGF-I + sex hormones
What are some examples of growth disorders?
Growth retardation
o Combined deficit of pituitary hormones
o Isolated growth hormone deficiency
o Insensitivity to growth hormone
o Hypothyroidism
o Hypercortisolism
Cushing’s diseaseʹ damage at the central level, high activity of adenohypophysis leads to overproduction of ACTH and excessive stimulation of the adrenal cortex
Cushing’s syndromeʹ excessive activity of the adrenal cortex, adenohypophysis tries to regulate it by decreased ACTH secretion but the adrenal cortex is ͞doing its own thing͟
Neurohypophysis
it has no gland structure, so it cannot synthesize hormones -> it only stores them
Antidiuretic hormone ADH ↑ retention of water by kidneys
Water/salt balance
oxytocin ↑ contraction of uterus +
mammary gland cells
Nervous system
Water balance disorders
Diabetes insipidus
o it is a disease caused by a lack of ADH / insensitivity of the receptors in the kidney which is manifested by polyuria
(no resorption of water in the kidneys = loss of liquids/ increased urine excretion) it also causes decrease in osmolality of
urine and increase of osmolality of serum (blood serum = yellowish liquid without cell elements -> formed after blood
clotting and subsequent clot removal)
o when the Glc high concentration is greater than 10mM, it is excreted in the urine
o thirst and associated polydipsia (compensation for dehydration ʹ drinking too much)
Diabetes insipidus centralis
o ADH-dependent; decrease in ADH)
o cause: insufficient secretion of ASH leading to CNS pathology
o treatment: ADH is substituted by desmopressin (a synthetically produced substance that is chemically similar to
ADH => a specific form of drug that contains desmopressin, eg Minirin => is also used in some forms of nocturnal
wetting in children and frequent forced urination at night in adults)
Diabetes insipidus renalis
o ADH-independent; increase in ADH
cause: renal receptor insensitivity - renal tubule disorder -> gene mutation: for ADH receptor for cellular water channel, aquaporin 2
o treatment: Sufficient fluid intake, sodium restriction in the diet, administration of diuretics (drugs that affect membrane transport in the nephron -> inhibit re-absorption of NaCl and water from the tubule)
Thyroid gland and parathyroid gland
T4 a T3
amine ↑ metabolism
TSH
calcitonin
peptide
↓ blood calcium level
Calcium in blood
Disorders of the function of the thyroid gland
Decreased hormone production (increase in TSH
a) Congenital hypothyroidism
thyroidal dysgenesis:
- can be caused by improper gland
development => agenesis (congenital
malformation of the organ ʹ generally
any part of the body) + aplasia
(malformation or lack of organ) +
hypoplasia (imperfect organ development)
- cystic malformation
- ectopia (= occurrence outside its usual location)
thyroidal dyshormonogenesis:
- impairment of any degree of hormone synthesis or secretion
b) acquired hypothyroidism
it is chronic autoimmune thyroiditis = Hashimoto’s thyroiditis
it is the most common cause of hypothyroidism -> relatively common disease affecting up to 5 % of the
population with a significant female prevalence (4:1)
treatment: hormone replacement
Increased hormone production (decrease in TSH)
o Autoimmune stimulation of TSH receptor ʹGraves-Basedow thyrotoxicosis
The body produces antibodies against TSH receptor -> after hormone binding the receptor is activated which leads to
hormone production
Parathyroid glands
parathormone (PTH)
peptide
↑ blood calcium level
Calcium in blood
Thymus
Thymosin
peptide
stimulates T lymphocytes
Adrenal glands
Adrenal medulla
Activates in acute stress
adrenalin, noradrenaline
amine
↑ blood glucose level
↑ metabolism vessel
constriction
Nervous system
Adrenal cortex
Activates under chronic stress
glucocorticoids
-cortisol (zona fasciculata)
↑ blood glucose level
immunosuppression
ACTH
mineralocorticoids
-aldosterone (zona glomerulosa)
↑ reabsorption of Na+
↑ excretion of K+ in kidneys
Kalium in blood
Adrenal cortex disorders
Reduced hormone production (increase in ACTH)
o Congenital adrenal hyperplasia (AR hereditary disorder of steroid
hormone synthesis)
Metabolic disorder with enzymatic block => one of the five necessary enzymes for steroid hormone synthesis is missing, leading to a deficit of a specific steroid group and at the
same time an excess of another group due to the over-production of ACTH
The most common deficiency is 21-hydroxylase (gene CYP21) -> up to 95 % of cases
-Decreased cortisol and aldosterone secretion
-salt-wasting
-elevated 17-hydroxyprogesterone level
o adrenal insufficiency (gland damage)
reduced production of cortisol and aldosterone
-autoimmune process (Addison’s disease) => formation of antibodies that damage the adrenal cortex
damaged adrenal glands can be due to genetics or infection ʹ e.g. meningococcal
infection causes both adrenal bleeding and complete destruction, which very often
leads to death (*adrenal bleeding = Waterhouse-Friderichsen syndrome)
Increased hormone production (decrease in ACTH)
o tumours
Cushing’s syndrome ; increase in cortisol)
- Manifested by obesity (fat mainly in the face and abdomen) increased appetite, the skin is
characterized by purple stretch marks, osteoporosis, DM2, depression
Conn syndrome ;increase in aldosterone
-Aldosterone producing adenoma
-Decreased sodium excretion (higher extracellular fluid volume, vascular fluid increase leads to hypertension, which is also associated with headache, fatigue, nasal bleeding which further leads to increased blood pressure and may also cause heart failure), increased potassium excretion (may occur) constipation, muscle weakness, heart rhythm disorders
Sex hormones
- Affect genital and secondary sexual characteristics
Adrenal cortex
- zona reticularis
androgens
– lead to hair production in
men and women
ACTH
Ovaries
- in follicle, corpus luteum
estradiol (+progesterone)
FSH + LH
Testes
- in Leydig cells
testosterone
LH
Regulation of reproduction
Reproductive axis: hypothalamus – pituitary – gonads
Three periods of reproductive axis activity:
o Fetal – maximum at week 20. (1/2) of pregnancy
Development of internal and external genitalia
o Infant – maximum between 3.-4. month
„physiological mini puberty “
development of sexually determined brain
o Pubertal and continuing adulthood
Development of secondary sexual characteristics (breast in women, genitalia in men, pubic hair in both)
the first two periods depend only on androgens (testosterone)
Reproductive disorders
Central premature puberty
o increase in sex hormones gonads (testosterone /aldosterone)
o gonadotropin-dependent disorder - an increase in FSH and LH secretion is required to start the disorder
o causes: hypothalamus, pituitary gland
premature activation of the reproduction axis
o isosexual: in accordance with biological sex
Peripheral premature pseudopuberty
o an increase in gonad sex hormones
o gonadotropin-independent disorder -decrease in FSH͕ and LH leads to increased sex hormone production without stimulus
o cause: gonads, adrenal glands
o heterosexual: masculinization of women, feminization of men
What is the McCune Albright syndrome?
- a reproductive disorder
The cause is a postzygotic activating mutation of the G protein α-subunit gene ->
Activation of hormone-stimulating receptor signal for melanocytes—-manifested as characteristic mapped skin lesions (ͣcafé au lait)
Activation of the parathyroid hormone (PTH) receptor signal -> bone fibrous dysplasia (spongiosis is replaced by connective tissue - the bones are then easily deformable)
Activation of FSH -> pseudopuberty receptor signal in girls, less often in boys
*clinical triad = this includes these symptoms => mapped skin lesions, bone fibrous dysplasia, isosexual premature pseudopuberty in women
Late puberty
o Lack of signs of reaching adolescence
o More common in boys,
is accompanied by a disorder of bone maturation and also a disorder of body growth
Hypogonadotropic hypogonadism (central)
decrease in gonad sex hormones
gonadotropin-dependent ; decrease in FSH͕ LH
causes: hypothalamus, pituitary gland
Hypergonadotropic hypogonadism (peripheral)
decrease in gonad sex hormones
gonadotropin-independent increase in FSH͕ and LH)
cause: gonads
Pancreas
Langerhans islets ʹ alfa cells produce glucagon /beta produce insulin
insulin
↓ blood glucose level
Glucose in blood
glucagon
↑ blood glucose level
Glucose in blood
Regulation of Glc levels in blood:
o increase: glucagon, adrenaline, cortisol, ACTH, growth hormone, thyroxine
o reduce: insulin, somatostatin
Glucose balance disorders
Diabetes mellitus
o Hyperglycaemia, glycosuria with glycaemia greater than, 10 mmol/l (glc in urine)
Diabetes mellitus 1. type
o cause: autoimmune destruction of β cells, leading to insulin deficiency
o typical occurrence already in childhood (in any case it is no exception that it develops at any time ʹ gradual development)
o it is generally a condition in which the blood glucose value is higher than 5,6 mmol —increased glucose concentration in extracellular fluid leads to an increase in osmolality, osmotic diuresis, polyuria (which leads to dehydration)
further manifested by increased ketone formation, acetone odour, lowering of pH—- acidosis (leads to respiratory centre irritation —Kussmaul breathing) - may result in coma
o therapy: insulin substitution
Diabetes mellitus Type 2
o It is a metabolic disorder in which glucose cannot be processed due to absolute or relative insulin deficiency and at the same time reduced tissue sensitivity to insulin ( = insulin resistance)
Manifested by polyuria, dehydration, thirst, hyperglycaemia, weight loss, fatigue, and vision problems, may also manifest as disorders of consciousness, susceptibility to infections, macrovascular (atherosclerosis…)
and microvascular complications (retinopathy, neuropathy.)
o cause: metabolic ʹ obesity
o therapy: diet + physical activity
Nerve tissue
- many cells (neurons and glial cells), little intercellular space
- function ʹ intake, analysis, integration, and transmission of information; coordination of organism functions
- irritability and conductivity ability of the cell to receive physical or chemical irritation and react to it by nerve impulse (excitement), which is evaluated in the cell and eventually forwarded
- neurons use both electrical (membrane depolarization) and chemical (synaptic) signaling
- transmission of excitement from receptor to effector = reflex
What does the neuron consist of?
- cell body (perikaryon, soma), dendrites and axon
What is the perikaryon of neuron?
o it is the trophic center of the neuron - supplies all its processes with the necessary substances
o nucleus - large, round, and light (mainly contains euchromatin and noticeably large nucleolus)
o Rough ER (in neurons it is called Nissl’s substance), polyribosome
o GA is only in the perikaryon, there may be several
o mitochondria mainly in axonal endings
o lipofuscin granules and melanin inclusions
