cell signalling - week 2 - part 1 Flashcards
Why do cells need to signal? (7)
- cell fate and decision making
- growth
- division
- motility
- secretion
- metabolism
- death
How do cells communicate?
- via chemical messengers
What are chemical messengers also known as?
signalling molecules
What exactly is the signal?
a ligand for a receptor
Where can messages be sent to?
- direct neighbouring via contact
- surrounding cells via diffusion
- much longer ranges
How does a cell respond to a signal?
- quickly via altered protein function
- slowly when changing gene expression
- both causes a cellular response
Why do we need membrane bound receptors?
2nd messenger is changed or produced in response to a primary messenger
Name the most common secondary messengers?
cAMP
cGMP
Ca2+
IP3
Nitric oxide
lipid metabolites
How do signals pass information?
- indirectly between more distant cells or directly between ada cent cells
Name four different ways in which signals can pass indirectly between more distant cells
- autocrine - cell to itself
- paracrine - cell to its neighbourhood
- endocrine - cell to another cell at a distance
- neuronal - via nervous system
Describe indirect cell signalling
- diffusion based
- chemical messenger/ signalling molecule secreted form a cell
- most molecules are secreted into aqueous fluid
- molecules transported over rein of distance
- signal binds to target receptor
- binding of signal causes response in target cell
Give examples o aqueous fluids most molecules are secreted into
- extracellular fluid,
- lymph
- blood
Give examples of where the target receptor the signal is going to bind to can be located
- inside the cell
- on the cell membrane
Describe autocrine signalling
- cell which producing ligand is also the target cell responding to the signal
- single leaves, but does not diffuse far (few microns only)
Describe paracrine signalling
- signalling cell send a signal to its direct neighbours
In paracrine signalling do the signalling cell and the target cell have to touch?
no
How far does the signal travel during paracrine signalling?
- short distances, normally in the same tissue
Give an example of paracrine signalling
immune cell recruitment and inflammation by mast cells:
- allergic reactions
- mast cells produce histamine which causes an inflammatory response
Describe endocrine signalling
- target cell and signalling cell separated by large distance
- gland secretes a hormone
- transported in circulatory system or lymph/ECF
Which routs can a signal take in endocrine signalling?
circulatory system (blood) but also lymphatic or ECF
Describe neural signalling
- nerve impulses travel long distances as electric impulses (fast) - action potentials
- chemical messages travel very short distance (slower) - synaptic transmission
How fast is the autocrine system?
shortest distance - msec to secs
How fast is the paracrine system?
shortest distance - msec to secs
How fast is the endocrine system?
long distance - secs to mins, maybe hours or even days
how fast Is the neural system?
long distances - mecs
name ways in which signals can pass information in direct ways between adjacent cells
- gap junction signalling
- juxtracirne signalling
Explain gas junction signalling
- signal pass via gap junctions form cytoplasm of one cell into cytoplasm of the next
how many connexions/ hemichannels does a gap junction require?
2
What is a hemichannel/ connexion made up of? How many?
6 connexin proteins
Does juxtracrine signalling require signal molecule movement?
No
How can signalling molecules be classified based on their biophysical properties?
either hydrophilic (soluble in aqueous solutions, eg. blood and lymph)
or hydrophobic (insoluble in hydrophilic solutions)
What allows hydrophilicity?
ability to travel directly in the blood, extracellular fluid or lymph
What does hydrophobicity require?
solubilisation by transport proteins in order to be secreted and travel to their target cell
What kind of receptor is targeted by hydrophobic signals?
generally intracellular (nuclear) receptors
What kind of receptor is targeted by hydrophilic signals?
generally, plasma membrane bound receptors, as the signal molecule is unable to pass through the lipid bilayer
name the 6 major classifications of signalling molecules
- peptides
- amines
- steroids
- lipids
- purines
- gases
Are peptides hydrophilic/hydrophobic?
hydrophilic
Are amines hydrophilic/hydrophobic?
either hydrophilic or hydrophobic
Are steroids hydrophilic/hydrophobic?
hydrophobic
Are lipids hydrophilic/hydrophobic?
hydrophobic
Are purines hydrophilic/hydrophobic?
hydrophilic
Are gases hydrophilic/hydrophobic?
hydrophilic
What three classes make up all known hormones and most of the known neurotransmitters?
first three - peptides, amine, steroids
What include peptides?
- single amino acids
- true peptides (at least 2 aa)
What can singe aa’s function as?
neurotransmitters
name three examples of neurotransmitters made up by a single amino acid
aspartic acid, cysteine, glutamic acid
How is glutamic acid processed?
via decarboxylation to form GABA
name examples of true peptide signals
neurotransmitters such as endorphin and hydrophilic hormones such as oxytocin
Where are all peptide signal molecules synthesised?
- translated from mRNA in the rER
- subject to post translational modification in Golgi
name examples of post translational modifications in the Golgi apparatus
- glycosylation - carbohydrate groups are added to a protein following its translation
How are peptide signal molecules transferred after the Golgi
- packaged into secretory vesicles
- released into extracellular space via exocytosis
- release either immediate or after some time
name a peptide signal molecule which is transferred out of the cell immediately after synthesis
cytokines
name a peptide signal molecule which is stored before release out of the cell
hormones and neurotransmitters
How do peptide signals act?
via cell surface receptors nd may have a number of different effects
Name two types of cell surface receptors
ionotropic and metabotropic
what if the membrane receptor is ionotropic?
binding of the signal to the receptor results in a change in ion flux into the cell
what if the membrane receptor is metabotropic?
binding of ligand to receptor results in a change in an enzyme’s activity within the cell
How do we stop the peptide signal from activating the receptor continually?
protease/peptidase enzymes are present to degredade the signal
What is the difference in degradation between simple and complex peptide signals?
- simple: rapid, signal may have a half life of only a few secs
- complex: eg. glycoproteins, slower, yield a half life measured in hours
if the half life of the protein signal is longer what does that mean regarding its synthesis?
they need to be continually synthesised by signalling cell in order to have a sustained signalling effect
What are biogenic amines?
- molecules, which contain an amine group (NH2)
- usually derived from amino acid
What amine is derived from tyrosine, is it hydrophilic/hydrophobic?
catecholamines (dopamine, octopamine, noradrenaline, adrenaline)
- hydrophilic -
What amine is derived from tyrosine derivative (thyronine), is it hydrophilic/hydrophobic?
thyroid hormone (thyroxine)
- hydrophobic -
What amine is derived from tryptophan, is it hydrophilic/hydrophobic?
indoleamines (serotonin and melatonin)
- hydrophilic -
What amine is derived from histidine, is it hydrophilic/hydrophobic?
histamine
- hydrophilic -
What amine is derived from choline, is it hydrophilic/hydrophobic?
acetylcholine
- hydrophilic -
Where is the neurotransmitter dopamine found?
in all taxa
Where is the neurotransmitter octopamine found?
invertebrates
Where is the neurotransmitter noradrenaline found?
vertebrates
What is adrenaline and where is it found?
both paracrine and endocrine hormone found in vertebrates
What is an example of indoleamines?
- serotonin (5HT)
- acts via 5HT receptors on plasma membrane
What can 5HT also be metabolised into?
melatonin
- neurotransmitter in most taxa
- associated with regulation of circadian and seasonal rhythms in vertebrates
- strong association with seasonal affective disorder (SAD)
Describe histamine
- neurotransmitter and also a paracrine signalling molecule in all taxa
- ## acts via a number of different plasma membrane receptors (diff response, diff tissue)
What effect does histamine have in vascular tissue?
results in vasodilation
What effect does histamine have in the bronchus?
results in bronchoconstriction
What is histamine also known for?
as a chemoattractant for mast cells - strongly associated with allergic responses
Acetylcholine is found in all taxa. Describe the receptors acetylcholine acts on
- acts via plasma membrane receptor
- nicotine ACh receptors are ionotropic, respond to signal binding by allowing ion flux into receiver cell
- metabotropic ACh receptors funciton by altering the metabotropic receptor GPCR
Where and in what form are thyroid hormones found?
- unique to vertebrates
- hydrophobic
- very small portion (<1%) free in blood, majority requires a carrier protein Ito be soluble within an aqueous fluid
Give an example of a thyroid hormone carrier protein and explain how they function?
- thyroxine binding globulin and albumin
- function by activating nuclear receptors which increases basal metabolic rate
What are steroids?
signal molecules that derive from cholesterol (hydrophobic 27C molecule)
In what forms do steroids exist?
- class of endocrine and paracrine hormones in all vertebrates (sex hormones) and many invertebrates (ecdysone)
- pheromones (communication between organisms)
name the five classes of steroid hormones
- progestins
- glucocorticoids
- mineralocorticoids
- androgens
- estrogens
give an example of a progestin, how many carbons?
progesterone (21C)
Give an example of a glucocorticoid, how many carbons?
cortisol (21C)
Give an example of a mineralocorticoid, how many carbons?
aldosterone (21C)
Give an example of an androgen, how many carbons?
testosterone (19C)
Give an example of an estrogen, how many carbons?
estradiol (18C)
All steroid hormones have 21 C true or false?
false - testosterone (19C), estradiol (18C)
Where are steroids synthesised?
mitochondria and sER
What attributes do all these steroid molecules have?
lipophilic
hydrophobic
What does it mean that all these steroid molecules are lipophilic?
- soluble in plasma membrane -> cannot be stored within vesicles or within cells
-> synthesised immediately prior to secretion
what does it mean that all these steroid molecules are hydrophobic?
- insoluble in aqueous fluids which surrounds cell
- to travel to site of action, require binding to carrier protein
What are common carrier proteins for steroid signalling molecules (hormones)?
binding globulin or albumin
How ua raw binding of the steroid hormone regulated to the carrier proteins?
by the laws of mass action and mass action equilibrium
What do the laws of mass action and mass action equilibrium state?
M+C <=> MC
M= messenger molecule
C= carrier
MC = messenger/carrier complex
What can be understood from the law of mass action equilibrium?
- source of signal, where conc is highest
- most chemical messengers will bind to carrier protein
- these contained in circulatory system - move away from source quickly to area where unbound messenger conc. is lower
-> unbinding f messenger form MC - int he unbound state again, messenger can interact with target cell
What do steroid signals bind to?
- nuclear receptors
where can nuclear receptors be found?
- in cytosol (class 1)
- within nucleus (class 2)
- in complex with the receptor
In complex with receptor what do steroid signals function as ?
transcription factors - also known as ligand dependent transcription factors
What are transcription factors able to do?
bind DNA and regulate gne expression via interactions with RNA pol
What are rarer signalling molecules?
lipids, purines, gases
(only rarer, not less important)
What are lipids, name the most important ones
- hydrophobic signalling molecules
- eicosanoids: 20C lipids
What includes eicosanoids?
- prostaglandins (PGs) and thromboxanes (TXs)
- leukotrienes (LTs), hydroxyeicostatetraenonic acid (HETEs), hydroperoxyeicostatertraenonic acid (HPETE’s), lipoxins
How are PGs and TXs synthesised?
by the action of cycloocygenase (COX)/ prostaglandin synthase (PTGS) enzymes
How are Lts, HETEs, HPETEs and lipoxins synthesised?
by lipoxygenase (LOX) enzymes
What lipids are important mediators in the inflammatory cascade? What do they do?
prostaglandins and leukotrienes
- signal to immune cells and vasculature
How can you characterise leukotrienes?
molecules made in leukocytes
characterised by three C=C double bonds
What is the lipid substrate for the cyclooxyrgenase and lipoxygenase pathways? Why?
the polyunsaturated fatty acid, arachidonic acid (AA)
- 20C fatty acid has 4 double bonds, all cis
What is arachidonic acid notation?
(C20:4)
How is arachidonic acid stored? Where?
esterfied (via carboxylic acid group) to glycerol in membrane phospholipids
How do you synthesis eicosanoids?
- first step: hydrolyse that ester bond,
- liberate that AA substrate from membrane phospholipids, by the action of phospholipase A2 (PLA2)
What do eicosanoids such as prostaglandins and leukotrienes do?
important for inflammatory cascade and mediating inflammation and nociception (pain signalling)
How to limit inflammation and/ or relieve pain:
(1) inhibit PLA2 using anti- inflammatory steroids - eg, glucocorticoid steroid hormone cortisol, or synthetic glucocorticoids (eg. hydrocortisone)
(2) inhibit downstream PTGS/COX enzymes using non-steroidal anti- inflammatory drugs (NSAIDs) eg. aspirin, ibuprofen, paracetamol
When prostaglandins are synthesised by AA, name their common intermediate
PGH2
What does PGF2alpha induce?
contraction of smooth muscle (eg. in vasculature and uterine myometrium)
How does PGF2alpha and PGE2 differ?
- differs only in having a ketone rather than a hydroxyl group at C9
What does PGE2 induce?
relaxes smooth muscle, acts all vasodilator rather than vasoconstrictor
Even though lipids, prostaglandins bind to and act ia cell surface receptors, what are they also?
G-protein coupled receptors (GCPRs)
How does PFG2alpha induce muscle contraction?
- binds to and activates PTGFR receptors
- these act via Gq G-protein, stimulating phospholipase C (PLC) - culminating in gen of intracellular second messenger inositol-1,4,5-trisphosphate (IP3)
- elevates intracellular calcium (Ca2+) conc
- induces muscle contraction
How can PGE2’s be mediated
- binds to and activates PTGER receptors - 4 cloned isoforms
- PTGER@ and PTGER4 act via Gs G-portein
- stimulate adenylyl cyclase (AC) - culminating ingenue of intracellular second messenger cyclic adenosine-3’,5’-monophosphate ()cAMP
- that activates protein kinase A (PKA)
- mediates intracellular response to PGE2
What are all prostaglandins reliant on?
presence of a hydroxyl group at C15
How do PGs rapidly inactivate?
- by the short chain alcohol dehydrogenase (SCAD) enzyme, 15- hydroxyprostaglandin dehydrogenase(PGDH)
- converting pivotal OH group at C15 to double bond ketone
- severely limits range of action - only autocrine/paracrine rather than endocrine hormones - they would rapidly inactivate if secreted into circulation by the PGDH enzyme
As what can the two purines, adenine and guanine exist in?
either nucleosides (adenosine and guanosine) or as nucleotides (AMP, ATP, GTP)
What are purines known as?
- to act as neurotransmitter or neuromodulators
- acting locally as autocrine/ paracrine hormones
Give an example of a purine in a mammal
both adenosine and extracellular ATP
What do adenosine and extracellular ATP do in a mammal?
- acting as a excitatory neurotransmitter to depolarise neurons
- lowers heart rate and hence cardiac output by signalling to cardiomyocytes
- autocrine action in leukocytes to modulate their activation as part of the immune response
- paracrine action on osteoblasts and osteoclasts to remodel bone (only in vertebrate)
How are purines limited by their metabolism?
- purine nucleotides are all subject to hydrolyses by ectonucleotidase enzymes - remove sequential phosphates form the nucleotide tri- di and monophosphate
-> limits purine to exert autocrine and paracrine (rather than endocrine) actions, or acting as neurotransmitter across synaptic cleft of purinergic neurons
How do purines activate transmembrane signalling?
bind to purinergic receptors
Where do adenosine and ATP act via?
metabotrophic GPCRs and also ionotropic receptors/ ligand-gated ion channels P2X receptors
Name three actions which involve ligand-gated ion channels
nociception
platelet aggregation
ejaculation
name three gases included in cell to cell communication
- carbon monoxide (CO)
- hydrogen sulphide (HS)
- nitric oxide (NO)
Why can gases pass through the bilayer?
even though they are hydrophilic, they are also very mall, so they can diffuse freely
What type fo receptor do gas molecules interact with?
intracellular proteins - due to size
How is NO synthesised?
form amino acid substrate arginine by NO synthase enzymes
What’s NOs half life?
short - only 2 to 30 secs
What does NOs short half life have for consequences?
- act locally on autocrine and paracrine manner
- doesn’t remain active long enough to travel any distance
Name NOs functions
- paracrine signal within immune system
- circulatory system: acts as vasodilator
How does NO act as a vasodilator?
- NO synthesised by NOS in vascular endothelial cell
- diffuses into vascular smooth muscle cell
- binds to soluble isoform of enzyme guanylyl cyclase
- this intracellular enzyme, changes confirmed on binding NO, catalyses conversion of GTP to cyclic guanosine3’,5’ monophosphate (cGMP)
- this activates protein kinase G (PKG)
- relates smooth muscle layer around blood vessel
- lower blood pressure
