TEST 3 Flashcards
how do bacteria receive and act on signals?
bacteria have membrane proteins that act as information receptors to generate responses such as:
- movement to and from stimuli
-formation of spores in conditions of nutrient starvation
what conditions do plant cells respond to?
variations in:
- sunlight
- growth hormones
- gravity
what are ligands called that stimulate pathways?
agonists
what are ligands called that inhibit pathways?
antagonists
name the 5 main types of receptor signalling
- direct contact
- gap junction
- autocrine
- paracrine
- endocrine
give a brief explanation of direct contact signalling
- a protein on the signalling cell binds to a protein on the target cell, and the target cell responds
- common in tissue development
what occurs in gap junction signalling?
- gap junctions exchange small signalling molecules and ions, coordinating metabolic reactions between cells
- used in electrical synapses
give an explanation of autocrine signalling
- the ligand induces a response only in the signalling cells
- often used to enforce developmental decisions, also a common feature of cancer cells
describe paracrine signalling
- neighbouring cells respond if they have the correct receptors for the ligand
- diffusion of the ligand is limited - it is destroyed by extracellular enzymes or internalised by adjacent cells
- occurs at the neuromuscular junction
give a brief description of endocrine signalling
- the ligand is produced by endocrine cells and is carried in the blood, inducing a response in distant target cells
- e.g. pancreatic functioning
how is specificity maintained (2 methods)?
1 - cell type specific expression and differential gene expression
- certain receptors are only present on certain cells, and molecules downstream of the receptor are only present in some cells
- genes can be turned on or off by interactions of activator or repressor regulators with enhancer of silencer control elements
2 - high affinity interactions
- there is a precise molecular complementarity between the ligand and the receptor, mediated by non-covalent forces
what is the equation for the equilibrium constant, what does it mean, and what are its units?
Keq = [RL]/[R][L]
- at equilibrium the rate of association and the rate of dissociation are equal
- the units are M^-1
- Keq is the affinity of molecules for each other
what is the equation for the dissociation equilibrium constant and what are its units?
Kd = [R][L]/[RL]
- Kd has the units of M
how does desensitisation occur in signalling pathways and when is sensitivity regained?
- when a signal is present continuously, the signal transduction pathway becomes desensitised
- when the signal falls below a threshold level, the signal regains sensitivity
what are the 5 main classes of receptors?
- receptors with intrinsic enzyme activity
- receptors linked to protein kinases
- receptors coupled to target proteins via a G protein
- intracellular receptors
- receptors that are ion channels
what hormones are required to regulate blood pressure, where are they found and what are their actions?
pancreatic:
- insulin - lowers BGL
- glucagon - raises BGL
adrenal:
- epinephrine - raises BGL
- cortisol - raises BGL
what function do acinar cells have?
digestive functions
what hormones in the islet of Langerhans are secreted by what cells?
- alpha cells secrete glucagon
- beta cells secrete insulin
- delta cells secrete somatostatin
what happens to the insulin receptor subunits following translation?
1 - they enter the ER membrane
2 - they associate into dimers
3 - they are exported to the cell surface via the golgi apparatus
4 - during intracellular transport, the proteins are processed by cleavage, each into an alpha and beta subunit
5 - at the plasma membrane, they are displayed as transmembrane proteins
define the term ‘first messenger’
an extracellular substance that binds to a cell surface receptor and initiates signal transduction that results in a change in intracellular activity
- they are also known as ligands
define ‘receptor’
- a protein that binds and responds to the first messenger
- receptors may be either displayed at the cell surface or may be intracellular
what occurs in insulin signalling when IR are activated?
1 - insulin binding stimulates an allosteric change in IR (autophosphorylation), bringing the cytosolic domain close and allowing activation
2 - activated IR phosphorylates and activates the insulin receptor substrate 1. the signal is transduced from the extracellular side to the intracellular side and is transferred to a soluble protein in the cytosol
3 - activated IRS-1 is bound by the adaptor molecules Grb2 and Sos, the signal is transferred to Sos (a nucleotide exchange factor)
4 - Sos converts inactive GDP bound Ras to active GDP bound Ras - the signal is transferred to the G protein Ras in the cellular membrane, activating Ras in the process
5 - activated Ras recruits Raf kinase to the membrane and activates its protein kinase activity. Raf phosphorylates and activates MEK kinase. MEK phosphorylates and activates MAPK - the signal has been transduced from the cytosolic face of the plasma membrane and amplified across the cytosol through a MAPK cascade
6 - activated ERK migrates to the nucleus and alters gene modulating expression of insulin responsive genes and causes expression of CDKs needed for mitosis
what is a second messenger?
- a small, metabolically unique molecule, not a protein, whose concentrations can change rapidly
- second messengers relay signals from receptors to target molecules in the cytoplasm or nucleus
what stages occur in glucose regulation?
1 - IRS-1 can activate PI-3K which phosphorylates membrane lipids
2 - membrane lipid PIP2 is phosphorylated by PI-3K to produce PIP3 (the second messenger)
3 - PIP3 recruits PDK1 which activates PKB
what are the responses in glucose regulation after PKB are activated
- there is an upregulation of glucose entry into cells and upregulation of glycogen production
- both growth and glucose metabolism can be coordinated via insulin signalling because there is a common intermediate
how is the glucose regulation pathway terminated?
a PTEN removes the phosphate at the 3 position of PIP3 to convert it into PIP2
- this shuts off signalling through PKB
what are the main symptoms of diabetes?
- excessive thirst
- frequent urination
- excretion of large amount of glucose in the urine
what is the basic structure of G-protein coupled receptors?
- extracellular domains - E1 and loops E2-4
- transmembrane domains - TM1-7
- cytosolic domain loops C1-C3 and C4 tail (C4 has a lipid anchor)
what is the result of a ligand binding to a G-protein coupled receptor?
1 - the GPCR forms a barrel shape and the ligand binding changes the orientation of the TM helices
2 - the heterotrimeric G protein is a timer of alpha, beta, and gamma subunits that is inactive when bound to GDP but active when bound to GTP. ligand binding alters receptor shape which induces nucleotide exchange from GDP to GTP
3 - following Galpha activation, the G-protein dissociates from the receptor to yield a Galpha-GTP and a tightly interacting Gbetagamma dimer
how is Galpha regulated in ligand binding?
- Galpha has a slow hydrolysis activity which regenerates the inactive form of the alpha subunit allowing reassociation with a Gbetagamma dimer to form the resting G protein
- this can again bind to a GPCR and await activation
what amount of each subunits do mammalian cells have?
- at least 20 Galpha subunits
- at least 5 Gbeta subunits
- at least 12 Ggamma subunits
what are some of the physiological responses in the fight or flight response?
- acceleration of heart and lung action
- palling or flushing
- general effect on the sphincters in the body
- dilation of blood vessels in muscles
- inhibition of tear and saliva production
- dilation of pupils and tunnel vision
- shaking
what is the role of cortisol in the flight or fight response?
- increases blood sugar through gluconeogenesis
- suppresses the immune system
what are the results of epinephrine on adrenergic receptors?
- binding to alpha adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenesis in the liver and the muscle, and stimulates glycolysis in the muscle
- binding to beta adrenergic receptors triggers glucagon secretion in the pancreas and increased lipolysis by adipose tissue
what chain of events occurs when epinephrine binds to adrenergic receptors?
1 - epinephrine binds a beta adrenergic receptor and activates a Gs
2 - removal of the ligand regenerates an inactive GPCR complex
3 - Gbeta inhibits adenylate cyclase but the alpha subunit stimulates adenylate cyclase
4 - this increases cAMP levels in the cell
- using cAMP, epinephrine induces glycogen breakdown in skeletal muscle and induces contraction in cardiac muscle
what occurs when epinephrine binds an alpha-adrenergic GPCR receptor coupled to a Gi heteromeric G protein?
- G alpha-i is activated and inhibits adenylate cyclase
- G betagamma-i subunits activate MAPK cascade
how is epinephrine terminated?
- adenylate cyclase acts as a GAP on Gas, converting the Galpha to its inactive form
what is the structure of the cholera toxin?
- cholera toxin has a catalytic A chain that sits in a ring of 5B subunits
- the A chain is processed by proteolytic cleavage to produce a catalytic chain (CTxA1) linked to CTxA2 that anchors the A1 chain in the B chain pentamer
- CTxA1 and CTxA2 are linked by disulphide bonds
how does the toxin act on the ER of cells?
1 - CTx binds the cell surface ganglioside lipid GM1 on target intestinal epithelial cells
2 - it then undergoes retrograde trafficking via endosomes and the Golgi complex to the ER
3 - at the ER, the disulphide bond between
what is leptin?
- leptin is a soluble factor released into the bloodstream by adipose tissue
- leptin binds leptin receptors in the hypothalamus and changes feeding behaviour
what gene is leptin the product of?
the Lep^OB gene
what behaviour is exhibited when the Lep^OB gene is inhibited?
- the physiology and behaviour of starvation occurs
- there are some similarities to the physiology of type II diabetes
what gene expresses the leptin receptor and where is it expressed?
- the Lepr^DB gene
- it is expressed in the hypothalamus
what is the function of leptin?
- it carries a message that fat reserves are sufficient
- it binds receptors in anorexigenic neurons in the hypothalamus and stimulates a signalling cascade that results in the release of alpha-melanocyte stimulating hormone that modulates the nervous system
what are the effects of leptin?
- suppression of appetite
- stimulation of the sympathetic nervous system:
– increased blood pressure
– increased heart rate
– increased thermogenesis
what occurs in the signalling pathway when leptin binds to the leptin receptor?
1 - leptin binds to the leptin receptor
2 - the ligand binds and dimerises the receptor, the dimerised receptor recruits protein JAK
3 - the receptor associates with JAK
4 - JAK phosphorylates Lep-R and activates it. the phosphorylation sites are used to recruit STATs
5 - STATs 3,5,6 are associated with the leptin pathway and are brought close to JAK
6 - JAK phosphorylates the fat STATs
7 - the phosphorylated STATs dimerise, exposing their nuclear localisation signals
8 - the dimerised STATs enter the nucleus and are not active transcription factors that modulate gene expression
9 - the precursor for alpha-MSH is made and processed to produce alpha-MSH
10 - alpha-MSH signals the next neuron to send a signal to the brain to stop eating
what are STATs?
STATs are latent transcription factors that are activated by JAKs
what are JAKs?
- JAKs are cytosolic, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway
- they possess 2 near identical phosphate transferring domains - one domain is a kinase, the other negatively regulates the kinase activity of the first
what is erythropoietin?
a hormone cytokine that controls the development of erythrocytes from precursor cells in the bone marrow
where is erythropoietin produced?
it is produced primarily in the kidneys
when is erythropoietin used?
- the kidneys measure haematocrit and sets it to 45%
- under hypoxic conditions, erythropoietin is secreted from the kidneys to increase erythrocyte production
when is erythropoietin used medically?
- it is only used in specific cases of anaemia caused by cancer treatments
how is EPO signalling controlled?
1 - via JAK-STAT pathway using STATs
2 - following JAK autophosphorylation, EPO signalling can access a Ras dependent pathway
- both mechanisms allow growth and development to be coordinated
describe the basic structure of G-protein coupled receptors
- there are 4 extracellular domains
- there are 7 transmembrane domains
- there are 4 cytosolic domains (3 loops and 1 tail)
- the tail has a lipid anchor
describe the process of ligand binding to G-protein coupled receptors
1 - GPCRs fold into a tertiary barrel structure and a ligand binds within the cavity. bulky ligands may bind to the extracellular loops or the N-terminal
2 - ligand binding changes the orientation of the TM helices
3 - ligand binding alters receptor shape, inducing nucleotide exchange of GDP to GTP
4 - the alpha, beta, and gamma subunits of the G-protein activate when bound to GTP
5 - after G alpha activation, the G protein moves from the receptor to make a Galpa-GTP complex and a G beta-gamma dimer
what number of each G protein subunit do mammals possess?
- at least 20 alpha subunits
- at least 5 beta subunits
- at least 12 gamma subunits
list some of the physiological responses involved in fight or flight
- acceleration of heart and lung action
- paling or flushing
- dilation of blood vessels in muscles
- inhibition of tear and saliva production
- dilation of pupils and tunnel vision
- shaking
what stimulates the physiological responses of fight or flight?
stimulated by the release of epinephrine and cortisol from the adrenal glands
what are the main effects of cortisol release?
- cortisol increases blood sugar through gluconeogenesis and suppresses the immune system
how does epinephrine bind to bring about a change?
- adrenergic receptors are GPCRs
1 - epinephrine binds a beta-adrenergic receptor and activates the G subunits
2 - the removal of the ligand regenerates an inactive GPCR complex
3 - G-beta inhibits adenylate cyclase but the alpha subunit stimulates adenylate cyclase
4 - epinephrine also binds an alpha-adrenergic GPCR receptor couples to a Gi heterotrimeric G protein. G beta-gamma-i subunits activate a MAPK cascade. G-alpha-i is activated and inhibits adenylate cyclase
5 - cAMP levels increase in the cell
how is cAMP used for epinephrine action
glycogen breakdown is induced in skeletal muscle and cardiac muscle contraction is induced
describe protein kinase A activation and action
1 - cAMP activates protein kinase A
2 - PKA binds 2 molecules of cAMP and becomes activated
3 - activated PKA targets proteins such as:
- transcription factors
- ion channels
- other enzymes
how is epinephrine terminated?
adenylate cyclase acts as a GAP on Galpha-s, converting the G-alpha to its inactive form
describe the structure of cholera toxin
- cholera toxin has a catalytic A chain that sits in a ring of 5B subunits
- the A chain is processed by proteolytic cleavage yo produce a catalytic chain disulphide (CTxAI) linked to CTxA2 that anchors the A1 chain in the B chain pentamer
describe the process of cholera toxin action
1 - CTx binds the cell surface ganglioside lipid GM1 on target intestinal epithelial cells
2 - it undergoes retrograde trafficking via endosomes and the Golgi complex to the ER
3 - at the ER, disulphide bonds between CTxA1 and CTxA2 is broken by protein disulphide isomerase
4 - binding protein keeps CTxA1 soluble until it dissociates across the ER membrane in an unfolded form
5 - CTxA1 refolds in the cytosol
what gives CTxA1 its toxicity?
- it is an ADP ribosylate
- the modified Galpha-s is locked on permanently and cannot degrade GTP
- cAMP builds up, activating CFTR channels causing efflux of water and severe diarrhoea
where does light pass through in the vertebrate eye?
- through the neural layer
- through the cell bodies of the light receptor cells
what are rod cells responsible for?
non-colour vision at low light intensity
describe the structure of rod cells
- the outer segment contains 1000 discs not connected to the membrane
- each disc is a closed sac of membrane with embedded rhodopsin molecule
what is Rhodopsin?
it is a specialised GPCR made of opsin linked to 11-cis-retinal
what is 11-cis-retinal?
a chromophore prosthetic group
how does cis-trans isomerisation cause Rhodopsin to become activated?
1 - alternating single and double bonds form a polyene with an unsaturated network of electrons than can absorb light energy
2 - light absorption causes cis-trans isomerisation around the C12 and C13 bonds- the N of the key lysine moves 0.5nm
3 - this alters the shape of the receptor
what does rhodopsin become when activated?
activated metarhodopsin
what is the role of metarhodopsin?
it stimulates nucleotide exchange on the alpha subunit of a specific heterotrimeric G-protein (transducin)
what occurs when transducin is activated?
1 - light activates rhodopsin which activates the G+ transducin
2 - the G protein dissociates and leaves the receptor, resetting back to inactive conditions
3 - G-alpha-T (GTP) stimulates cGMP phosphodiesterase which removes cGMP from cGMP-gated ion channels
4 - the GMP produced stimulates the closing of the ion channels, hyperpolarising the membrane
describe the extent of rhodopsin’s sensitivity
- a rod cell can respond to 1 photon
- it takes 5 of these signals to reach threshold potential
what is the peak absorbance of rhodopsin?
500nm
how are rod cells inhibited under high light intensity?
1 - light closes the cGMP gated ion channels, reducing the influx of Ca2+
2 - Ca2+ is removed by Na/Ca antiporters so concentration of Ca in the cell falls
3 - low Ca2+ activates guanylate cyclase
4 - cGMP levels rise so the channels reopen
what can occur to rhodopsin at high light intensities?
rhodopsin can be phosphorylated by rhodopsin kinase
what reduces the activation of transducin?
rhodopsin phosphorylation
how many phosphorylation sites are there on rhodopsin?
there are 7
the higher the light intensity the more sites are phosphorylated
which visual pigments do humans possess?
- blue
- green
- red
how does sildenafil citrate cause blue tinged vision?
- it has a very similar structure to cGMP
- it inhibits PDE-6
how do intracellular receptors act as enzymes?
1 - an extracellular ligand diffuses across the plasma membrane and binds and activates its receptor
2 - the receptor converts its substrate into a product and the activity of downstream targets is altered
when was it found that nitric oxide relaxes smooth muscle?
1977
when was it discovered that Ach induces the release of endothelium deriving relaxing factor (EDRF)?
1980
how does nitric oxide signal in the body?
1 - the gas NO* diffuses across the membrane and binds and activates its receptor, guanylate cyclase
2 - GC converts GTP into cGMP
3 - cGMP is a second messenger
what is the primary treatment of angina?
glyceryl trinitrate - causes blood vessel dilation
how is NO* production in vivo stimulated by high blood pressure?
1 - autonomous nerves in the vessel wall respond to high blood pressure high shear and release Ach
2 - ACh binds its receptors on the endothelial membrane which increases CA2+ concentration
3 - high Ca2+ concentration activates nitric oxide synthase
4 - NOS catalyses the conversion of arginine to citrulline and nitric oxide
5 - NO* activates guanylate cyclase which converts GTP to cGMP
6 - cGMP activates protein kinase G in the smooth muscle
why can NO* only communicate over short distances in the body?
it is an unstable compound so has a short half life
what compound is EDRF?
NO*, found out in 1987
what is the action of protein kinase G after being activated by cGMP?
- it phosphorylates myosin light chain, relaxing the muscle
- smooth muscle relaxation causes blood vessel dilation which lowers blood pressure
what signalling pathways is nitric oxide involved in?
- control of capillary dilation
- control of blood vessel dilation
- control of peristaltic movement through the gut
- regulation of glomerular capillary pressure
- regulation of blood flow in the adrenal glands
- regulation of muscle contraction and blood flow in erectile tissue
do all signalling pathways using nitric oxide use responses via cGMP-dependent protein kinases?
no, there are also cGMP-gated ion channels and cGMP-dependent phosphodiesterases
what are the NOS1, nNOS neuronal isoforms used for in the body?
- development of the nervous system
- protection against cardiac arrhythmia induced by myocardial infarction
- peristalsis
- sexual arousal
what are the NOS2, iNOS inducible isoforms used for?
- producing large amounts of NO* as a macrophage defence mechanism
- cause of septic shock
what are the NOS3, eNOS endothelial isoforms used for?
- controls vascular tone
- insulin secretion
- regulates angiogenesis
- plays a critical role in embryonic heart development and morphogenesis of coronary arteries and cardiac valves
what is a recreational use of NO*?
poppers
what can be prescribed to treat a weak heart?
- an amyl nitrate inhalation spray which vaporises to produce NO$
what are cyclic nucleotides?
important secondary messengers that control physiological processes including smooth muscle contractility
what are phosphodiesterases?
a superfamily of metallophospy hydrolases that cleave cAMP and cGMP to produce the corresponding 5’ nucleotides
what are the 4 types of eostrogen?
- oestrone - predominant in the menopause
- oestradiol - predominant during the reproductive years
- oestetrol & oestriol - predominant in pregnancy
what type of hormones are eostrogens?
steroid hormones
describe the structure and placement of the oestrogen receptor (ER)
- it has an N-terminal transactivation domain, a DNA-binding domain, and a hormone binding domain
- it is stored in the cytosol in complex with a dimeric, chaperone protein, and Hsp90
-> Hsp90 bind near the ligand binding site and maintains the ER in a soluble (it is too large to enter th nucleus)
what occurs in eostrogen signalling?
1 - oestrogen diffuses across the plasma membrane and binds ER
2 - ER is released from Hsp90
3 - the ER-oestrogen complex enters the nucleus and binds oestrogen response elements as a dimer
4 - eostrogen-responsive genes are transcribed
why is there no amplification in oestrogen signalling?
the ER is both the receptor and effector
what are the roles of ERs in reproduction?
females - induction of progesterone receptor, cell differentiation, ovulation, implantation, pregnancy maintenance, childbirth
males - normal testicular function, fertility, sperm morphology
what are the roles of ERs in the cardiovascular system?
- lipid profiles
- fat distribution
- the tone of vascular and smooth muscle cells
- endocrine factors produced by the vascular wall
- fibrinogen levels
- blood platelets
- inflammatory factors
- coagulation
what are the roles of ERs in the immune system?
- ERs are expressed in primary lymphoid organs and peripheral immune cells
- thymus development
- enhancement of the humoral immune response
what are the roles of ERs in the central nervous system?
- oestrogens influence cognitive function
- specific differentiation of the hypothalamus
- growth factors that influence brain development, cell survival, and neural plasticity
what are the roles of ERs in the skeletal system?
- bone modelling in adolescence
- initiating pubertal bone growth and limiting longitudinal bone growth in females
- maintenance of bone mass
what are the different isoforms of the ER?
- there are two isoforms - alpha and beta
- they are encoded by separate genes (ESR1 and ESR2 respectively)
- there are homodimers and heterodimers of each
- there are also splicing variants
what is GPER and its function?
- it is a type of GPCR
eostrogen binds GPER to stimulate multiple pathways: - ligand-independent activation of ER
- release of EGF via Ca2+ as a second messenger
- stimulation of the MAPK signalling pathway via interaction with Grb2
how can the oestrogen pathway be inhibited to treat breast cancer?
- tamoxifen is used in ER+ breast cancer females and breast cancer males
- it is an ER antagonist that inhibits signalling via ERs and causes cells to remain in the G0 and G1 phases of the cell cycle
- some breast cancers become resistant to tamoxifen since GPER can stimulate oestrogen responsive growth independently of ER
what does the sensory system include?
- sense organs
- sensory nerves
- central sensory areas
what does the motor system include?
- motor neurons
- central motor areas
- all muscles and ducted glands of the body
what does the neuron doctrine (1894) state?
1 - the neuron is the structural and functional unit of the nervous system
2 - neurons are individual cells which are not continuous to other neurons
3 - the neuron has 3 parts - dendrites, soma, and axon
4 - conduction takes place in the direction from dendrites to soma, to the end abhorisations of the axon
what are the functions of the functional units within the neuron?
dendrites - increase surface area, receive inputs
axons - carries info over distances
myelin - coats axons, improves conduction
nodes of ranvier - breaks in the myelin sheath
terminals - output regions where transmitter is released in the synapse with other neurons
where does anterograde transport in the neuron? what is its speed?
- from soma to terminals
- can be rapid or slow
where does retrograde transport in the neuron? what is its speed?
- from terminals to soma
- only rapid
what do both retrograde and anterograde transport require?
- hydrolysis of ATP
- microtubules
what are the functions of Glia?
- form the myelin sheath in the central NS - oligodendrocyte
- act as scavengers to clear up cellular debris and launch an immune response - microglial cells
- astrocytes mop up transmitters, correct ionic environments, release gliotransmitters, provide metabolic fuel for neurons
what is the equation of the encephalisation quotient?
brain weight / body weight
what are the different segments of the spinal cord?
- cervical
- thoracic
- lumbar
- sacral
what does the brain structure look like in a 4 week old embryo?
- the forebrain (prosencephalon), midbrain (mesencephalon), and hindbrain (rhombencephalon) are forming
- beginning of the spinal cord
what does the brain structure look like in a 6 week old embryo?
there are further divisions:
- prosencephalon is divided into the diencephalon and telencephalon
- development of the eye and ventricles (fluid filled cavities in the brain)
in the adult brain structure, what does the diencephalon form?
- thalamus
- hypothalamus
in the adult brain structure, what does the telencephalon form?
- basal ganglia
- hippocampus
in the adult brain structure, what does the mesencephalon form?
- inferior colliculus
- superior colliculus
- ret formation
in the adult brain structure, what does the rhombencephalon form?
- medulla
- cerebellum
- pons
what are the 3 layers of the meninges?
1 - dura mater
2 - arachnoid mater
3 - pia mater
what is the principle source of cerebral spinal fluid?
the ventricular system
where is cerebral spinal fluid made?
it is made by choroid plexus in ventricles
what are the functions of the cerebral spinal fluid?
- it supplies the brain and spinal cord with nutrients
- buffer changes in blood pressure and protects the brain
- supplies brain with fluid during dehydration
- allows the brain to remain buoyant
- large amount of protein contained
what links the 2 hemispheres of the brain?
the corpus callosum
what does the midbrain control?
- visual and auditory info
- motor control
- sensation
what does the pons control?
- links with the cerebellum and modifies medulla output
what does the medulla control?
- respiration
- cardiovascular function
what does the cerebellum control?
- balance
- gait
- fine movement
- posture
what does the thalamus control?
- it integrates sensory info
what does the hypothalamus control?
- autonomic control
- reproductive behaviour
- homeostasis
- endocrine control
what is the resting membrane potential?
-70mv
what does resting membrane potential require?
- an intact cell membrane
- ionic concentration gradients and permeabilities
- metabolic processes
what does resting membrane potential require?
- an intact cell membrane
- ionic concentration gradients and permeabilities
- metabolic processes
what ion flow occurs during action potentials?
1 - around threshold Vm, the membrane becomes more permeable to Na+ ions
2 - this leads to depolarisation and recruitment of Na+ channels
3 - depolarisation results in Na+ channel inactivation
4 - after a delay, K+ channels open
5 - the membrane repolarises
how are voltage gated Na+ channels inactivated?
1 - positively charged activation gate keeps channel closed
2 - depolarisation of the membrane causes activation gate to swing, allowing Na+ ions to enter
3 - the inactivation ball enters the channel to block Na+ influx
what occurs in the absolute refractory period?
- it is not possible ot elicit another action potiential
- due to Na+ channel inactivation
what occurs in the relative refractory period?
- action potentials can be elicited but require stronger or longer stimulations
what is the point of the refractory period?
- it ensures the action potential travels in one direction
where are action potentials initiated?
at the axon hillock
what is the use of saltatory conduction?
- myelination greatly accelerates action potential velocity
- action potentials only occur at the nodes of Ranvier, where there is a large density of Na+ channels
- saltatory action potential leaps instead of passing along the axon as Na+ diffuses alongside of the axolemma to the next node where the next action potential is generated
what is a synapse?
a junction where information is passed from one neuron to another
what are chemical synapses?
where chemicals are released from the presynaptic neuron to modulate the postsynaptic neuron
what are the features of electrical synapses?
- no delay
- can be 2 way
- little plasticity
what are the features of chemical synapses?
- delay
- one way
- history dependent plasticity
what do vertebrates possess in their gap junctions?
connexins
what do invertebrates possess in their gap junctions?
innexins
what amino acids are used as neurotransmitters?
- GABA
- glutamate
what amines are used as neurotransmitters?
- noradrenaline
- dopamine
- serotonin
what are some neurotransmitters that are not amino acids or amines?
- ATP
- acetylcholine
- nitric oxide
what are the 3 types of chemical synapses?
- axodendritic
- axosomatic
- axoaxonic
where are non-peptide neurotransmitters synthesised and transported?
- synthesised in the nerve terminal
- transported into a vesicle (a proton gradient drives vesicle filling)
where are peptide neurotransmitters synthesised and transported?
- synthesised in the cell body
- transported to the terminals in vesicles
how are vesicles docked to the membrane?
- a combination of SNAP and SNARE proteins anchor vesicles to the presynaptic membrane
how does calcium enter the nerve terminal?
the action potential:
- depolarises the nerve terminal via Na+ channels
- opens voltage gated Ca2+ channels
- Ca2+ moves into the nerve terminal
how do docked vesicles fuse and release neurotransmitter?
- Ca2+ binds to SNARE protein synaptotagmin
- exocytosis occurs - 3-5 Ca2+ ions are needed
what receptors can neurotransmitter bind to?
- channel-linked receptors (inotropic)
- G-protein coupled receptors (metabotropic)
- kinase linked receptors
- receptors linked to gene transcription
what does binding to ionotropic receptors lead to?
hyperpolarization or depolarisation
what does binding to G-protein coupled receptors lead to?
it sets off second messenger cascades
how are neurotransmitters produced?
- acetyl CoA and choline produce acetylcholine and CoA
- enzyme: choline acetyltransferase (CHAT)
what are the general properties or neurotransmitters?
- it must be synthesised in the neuron
- slow activity - dependent on release from the terminal
- duplicate effects of stimulation when applied exogenously
- actions blocked by competitive antagonists in a concentration-dependent manner
- can be removed from the synaptic cleft by specific mechanisms
how many pairs of spinal nerves are there in humans?
31
where are motor neuron cell bodies situated?
in the ventral horn of the spinal cord
what % of neurons cross over in the medulla?
70%
what do motor units consist of?
- a single motor neuron, neuromuscular junctions, and muscle fibres
how many types of skeletal muscle are there in motor units?
3
what are the features of type 1 slow oxidative skeletal muscle?
- slow contraction speed
- low generative force
- small motor units
what are the features of type 2 fast oxidative skeletal muscle?
- intermediate contraction speed
- intermediate generative force
- intermediate sized motor units
what are the features of type 3 fast glycolytic skeletal muscle?
- fast speed of contraction
- high force generated
- large motor neurons
how can force of contraction be increased?
- recruitment - small motor units are recruited first, increasing the number of units contracting
- temporal summation - twitches are stimulated more often causing a tetanus (a sustained contraction)
why do muscles show fatigue?
as a protective/defence mechanism
what are the causes of muscle fatigue?
- depletion of oxygen
- accumulation of extracellular K+
- accumulation of lactate
- accumulation of ADP + Pi
- central fatigue occurring in the brain
how do stretch receptors control muscle tension?
- golgi tendon organs in the tendon detect contraction and send info to the spinal cord
- muscle spindles detect stretch
- spindles become loose in contraction and the gamma motor neurons keep them taught
where do sensory neuron cell bodies sit?
in the dorsal root ganglion
what are the different types of sensory receptors?
- mechanoreceptors
- pain receptors
- thermoreceptors
- chemoreceptors
- photoreceptors
what are the two types of receptor adaptation?
tonic - slowly adapting
phasic - rapidly adapting
what is a receptive field?
an area on the skin where a sensory neuron can be activated
what are the two types of muscle contraction?
isometric - increase in tension but no change in length
isotonic - no tension change, length shortens to overcome the load
what is the structure of cardiac muscle?
- electrically coupled vie gap junctions
- linked together via intercalated discs
- contain sarcomeres, T. tubules, and SR
what are the general properties of cardiac muscle?
- have different properties depending in location
- striated
- show myogenic activity
- cells are electrically coupled
- have a T system
- controlled by the autonomic nervous system and hormones
what is the structure and properties of smooth muscle?
- makes up internal organs
- heterogenous
- maintains a steady level of tension
- produces slow, long lasting contractions
- spindle shaped cells are present which are linked together by mechanical and electrical junctions
- there are no cross sections but actin and myosin held in a loose lattice
- innervated by the ANS
- plastic properties
what are the patterns of contraction in smooth muscle?
- fully contracted most of the time in sphincters
- partially contracted in blood vessels and airways
- phasically active in stomach, intestines, and uterus
- mainly relaxed in the bladder
how is smooth muscle controlled?
- can be multi unit or single unit:
-> multi unit - each cell on the muscle is controlled separately
-> single unit - one signal is propagated to all cells in the muscle fibre through gap junctions
what is the structure of skeletal muscles?
- alignment of the sarcomeres gives a striated appearance
- contain many nuclei
- moves by the sliding filament mechanism
what does the contraction force depend on?
- number of active muscle fibres
- frequency of stimulation
- rate at which muscle shortens
- cross sectional area of the muscle
- initial resting length of the muscle
what is the structure of the T system?
- a triad junction occurs at the junction of A and I bands
- myosin is the thick filament
- actin is the thin filament
describe the cross bridge cycle
1 - ATP binds to the myosin head, causing dissociation of the actin-myosin complex (released state)
2 - ATP is hydrolysed, causing myosin heads to return to their resting conformation (cocked state)
3 - a cross-bridge forms and the myosin heads bind to a new position on actin, contraction is controlled here (cross bridge state)
4 - phosphate is released, myosin heads change conformation resulting in the power stroke. actin is drawn along myosin and the filaments slide pas each other (power stroke state)
5 - ADP is released - attached state
what are the main sources of ATP for muscle contraction?
- phosphocreatine
- glycogen
what are the features of slow twitch fibres?
- metabolise via oxidative phosphorylation
- high number of mitochondria
- high glycogen storage
- slow contraction and relaxation rates
- can maintain tension for prolonged periods of time
- resistant to fatigue
what are the features of fast twitch fibres IIA?
- metabolism via oxidative phosphorylation
- very high number of mitochondria
- high glycogen stores
- fatigue resistant
what are the features of fast twitch fibres IIB?
- anaerobic glycolytic metabolism
- fewer number of mitochondria
- high glycogen storage
- rapid fatigue
- required for short periods such as sprinting
why are calcium ions required for muscle contraction?
- calcium binds to troponin C, causing a conformational change to move tropomyosin, allowing myosin to bind to the actin head
how does calcium leave the sarcoplasmic reticulum?
1 - membrane depolarises, opening L-type Ca2+ channels
2 - mechanical coupling between the L-type Ca2+ channel and the Ca2+ release channel causes the Ca2+ release channel to open
3 - Ca2+ exits the SR via the Ca2+ release channel and activates troponin C, leading to muscle contraction
4 - Ca2+ entering the cell via L-type Ca2+ channels also can activate the Ca2+ release channels
how is muscle contraction terminated?
1 - small amounts of Ca2+ os extruded from the cell
2 - most Ca2+ is taken up into the SR by SERCA type pump
what are the main valves in the heart?
- tricuspid valve separates the right atria and right ventricle
- mitral (bicuspid) valve separates left atria and right ventricle
- pulmonary valve separates right ventricle from the pulmonary circuit
- aortic valve separates left ventricle from aorta
what is systole?
- ventricular contraction
- 70ml of blood is pumped from each ventricle
- lasts around 300ms
what is diastole?
- relaxation allows filling of the heart
- lasts around 550ms
- principle filling occurs in the first 100-200ms and is passive during this time
how is mean arterial pressure calculated?
1/3 systole + 2/3 diastole
what valves are open in systole?
- pulmonary valve
- aortic valve
what valves are open in diastole?
- tricuspid valve
- mitral valve
how is cardiac output calculated?
stroke volume x heart rate
what is starling’s law?
energy of contraction is a function of the length of the cardiac muscle fibres
what is the conduction pathway in the heart?
- pacemaker in sinoatrial node sends impulse which travels to the AV node
- travels to ventricles through Purkinje fibres of the bundle of His and their branches, and then throughout the myocardium
- includes a pause at the AV node of 130ms
what are myocytes?
- branched muscle cells with a single central nucleus
- cylindrical
- striated appearance under a microscope
- connected by tight junctions coupled through connexins
- contraction is activated by Ca2+ entry
- action potentials propagate through electrical connections in the gap junction
how is the electrical potential dependent on calcium?
- resting membrane potential is determined by K+
- depolarisation is determined by a reduced K+ and increased Ca2+ permeability
- occurs through K+ channels and non selective cation channels
- phase 4 depolarisation occurs in sinoatrial node
- ventricles have a slow depolarisation
what prevents tetanus in cardiac muscle?
a long refractory period
how is an ECG read?
p wave - contraction of the atria
qrs complex - contraction of the ventricles
T - diastole
- repolarisation of the atria happens during QRS
what are the different layers of a blood vessel?
(inner to outer)
- lumen
- tunica intima - endothelium, supportive connective tissue, release of paracrine signals
- tunica media - elastic tissue, smooth muscle
- tunica adventitia - principally collagen
how is energy stored and released in arteries?
- energy is stores in the tunica media
- the energy stored during systole is released in diastole, maintaining blood flow at this time and smoothing it
what 3 factors determine resistance?
- length of blood vessels - longer blood vessels provide greater resistance
- viscosity of blood - blood with a lot of solute would provide more resistance
- radius of blood vessels
what movement does blood flow usually follow?
laminar
what control access to microcirculation?
sphincters
what is anastomoses?
bypassing from arteries to veins through capillaries
how is fluid lost and gained into capillaries?
- loss of fluid is due to hydrostatic pressure
- reabsorption is due to colloid osmotic (oncotic) pressure
filtration pressure =
hydrostatic pressure - oncotic pressure
where does extra fluid go?
- taken into the lymphatics
- lymphatic system samples blood for foreign particles
- larger lymphatics have valves and contract rhythmically
does the pulmonary circuit hold extra volume?
nope
what is orthostatic intolerance?
when the blood pressure cannot be raised fast enough to match need
what is the heart innervated by?
sympathetic and parasympathetic
what are blood vessels innervated by?
sympathetic
what does the sympathetic arm drive through noradrenaline?
- increased heart rate - positive chronotropic effect
- increased conduction - positive dromotropic effect
what does the parasympathetic arm slow through acetylcholine?
- decreased heart rate - negative chronotropic effect
- decreased conduction - negative dromotropic effect
which system influences contractility?
only sympathetic
where in the blood vessel does the sympathetic nerve innervate?
the tunica media
why do sympathetic nerves tonically release noradrenaline?
to:
- control resistance of systemic circulation
- regulate flow to organs or tissues
where does noradrenaline act?
- acts on alpha and alpha 2 receptors to mobilise Ca2+ in smooth muscle
MLCK (myosin light chain kinase) - causes phosphorylation and therefore contraction
MLCP (myosin light chain phosphatase) - removes a phosphate group and causes inhibition of MLCK
what are baroreceptors and how do they maintain blood pressure?
- generally si in the aortic arch and carotid body
- information is taken and fed to the nucleus tractosocitarius
- if the pressure needs to be increased, a signal is sent through the CVLM and RVLM in the sympathetic pathway and then ot the intermediate lateral cell column in the spine, and is then passed to the heart by sympathetic nerve fibres
- to decrease pressure, a signal is sent to the DVMN and nucleus ambiguus and then to the vagus efferents
how is blood volume regulated by the body?
- renin is secreted by the kidney
- the sympathetic nervous system sends impulses, which decreases perfusion of the kidney when blood pressure is too low, stimulating renin secretion
- renin is released into bloodstream
- angiotensinogen is acted on by tenin to cleave to angiotensin I
- angiotensin I is converted to angiotensin II in the lungs by ACE
- angiotensin II works
what does angiotensin II do?
- constricts glomerular efferent arteriole and increases Na+/H+ exchanger activity
- ADH secretion
- hypertension
- stimulates thirst
- aldosterone secretion
what does aldosterone do?
- retention of Na+
- thirst
- ECF and plasma volume
- filling pressure
how do stretch receptors reduce ECP volume and blood volume?
1 - the atria secrete atrial natriuretic peptide
2 - causes renal excretion of Na+ and reduction of ECF volume
3 - sends info to hypothalamus to decrease secretion of ADH
what happens under hypoxia to cause vasodilation?
- K+ is released and adenosine
why does the pulmonary circuit have low resistance?
- short distance
- large diameter
how do lungs respond to hypoxia to match perfusion to ventilation?
hypoxia in the lungs closes TASK channels to prevent adenosine release to cause contractions
how does the body try to respond to hemorrhage?
- renin will be produced and this pathway corrects for loss of blood volume
- reabsorption of interstitial fluid partly restores blood volume
- secretion of erythropoietin will restore rbc count
how does cardiovascular system respond to exercise?
1 - provide skeletal muscle with radically increased blood supply
2 - raise cardiac output and balance changes in peripheral resistance
3 - increase coronary blood flow
how does local vasodilation occur in exercise?
- K+ relaxes vascular smooth muscle (electrical activity releases K+ so plasma K+ concentration rises in exercise)
- ATP is converted to adenosine and acts as a paracrine vasodilator
- lactate is produced in anaerobic respiration so acidification leads to vasodilation
why do starling’s laws not apply during exercise?
increases in filling pressure during exercise would lead to overstretching cardiac muscle
- reduction in diastole during exercise protects the heart from overfilling
what is external respiration?
the exchange of oxygen and CO2 between and organism and external environment
what is breathing?
the act of muscle contraction/relaxation to move air in and out of the lung
what is ventilation?
movement of air from outside to inside the body for exchange of gas between air in the lungs and blood in capillaries within the alveoli
what are the 3 controls of breathing?
- reflex/automatic
- voluntary/behavioral
- emotional
where is inspiratory rhythm generated?
pre Botzinger complex
where is expiration rhythm generated?
by the parafacial respiratory group
what coordinated reflex control of breathing?
the ventral respiratory column
where does voluntary control of breathing originate?
in the motor cortex
when can voluntary control not be maintained?
when Pco2 or H+ become too high
what does emotional control of breathing arise from?
corticospinal projections
how does acidification help regulating minute breathing?
- the ability of arterial PCO2 to control breathing is largely due to associated changes in H+ when oxygen binds to haemoglobin
- CO2 is directly detected
- both central and peripheral chemoreceptors respond to high arterial PCO2
which modulates breathing at a higher extent, hypoxia or hypercapnia?
hypercapnia
where are the peripheral chemoreceptors and what do they detect?
- carotid bodies
- aortic bodies
- about 80% O2 detection and 20% CO2 detection
where are the central chemoreceptors and what do they detect?
- mainly located in the medulla oblongata but can be in other brain structures
- respond to changes in cerebrospinal fluid
- 70% CO2 detection, 30% O2 detection
what complexes do blood gas regulation involve?
- Raphe complex and CPPy in adults detect CO2
- glia send CO2 and O2 signals. throughout the medulla
- glia in the RTN complex detect pH
- RTN also detects CO2 at birth
what is responsible for the fear response to CO2?
amygdala
what are the main features of slowly adapting stretch receptors?
- minotor lung inflation
- in smooth muscles of bronchi and trachea
- stimulated by stretch
- inhibit inspiration and lengthen expiration (Hering-Breuer inflation reflex)
what are the main features of rapidly adapting pulmonary stretch receptors?
- in epithelial cells in larynx, trachea, and airways
- respond to mechanical stress
- respond to the chemical environment of the lungs; noxious gas, dust, cold, histamine
- constrict airways and promote rapid shallow breathing
- responsible for the gasping inspiration in newborns
- promote cough in the trachea and larynx
- promote sighing due to gradual collapse of the lungs (atelectasis)
what is compliance?
it is the ability to expand the lungs in any given change in pulmonary pressure
what are the determinants of lung compliance?
- stretchability of tissues
- surface tension within alveoli
how is surface tension in alveoli altered?
- lowered by pulmonary surfactant and increased compliance
- pulmonary surfactant is released from type II alveolar cells during sighing
what is the cough reflex caused by?
the receptors in epithelial cells of upper airway
what is the sneeze reflex caused by?
the receptors in epithelial cells of nose or pharynx
how does cardiovascular system respond to exercise?
1 - provide skeletal muscle with radically increased blood supply
2 - raise cardiac output and balance changes in peripheral resistance
3 - increase coronary
