Extracellular Receptor Signalling Pathways Flashcards
Describe signal transduction
Extracellular signal molecule activates membrane receptor
Transduced via certain pathway
Activate cellular response
What is the pathway for signal transduction
External signal Receptor Transducer Amplifier Response
What are extracellular signal molecules?
“1st messenger”
What are intracellular molecules?
“2nd messenger”
What are membrane proteins?
Transducers
What do membrane proteins (transducers) do?
Converts messages of extracellular signals into intracellular messages
What are some cellular responses?
Altered ion transport Altered metabolism Altered gene expression Altered cell shape or movement Altered cell growth + division
What are some chemicals that serve as extracellular signalling molecules?
Amines
Peptides
Steroids
Other small molecules - eg. amino acids, ions + gases
What are the 4 main classes of receptors?
Ligand-gated ion channels
G-protein coupled receptors
Enzyme-linked receptors
Nuclear receptors
What happens when signal molecules bind to ligand-gated ion channels?
Conformational change = OPEN
What are ionotropic receptors (nicotinic acetylcholine receptors)?
Ligand gated ion channels that mediate effects of acetylcholine on muscle
What happens when acetylcholine binds to ionotropic receptors?
Na+ enters
Binds to nicotine
Electrical event (inward Na+ current) = triggers response
Ca2+ may enter
What is GABA A selective for?
Cl-
What is GABA A activated by?
y-amino butyric acid - CNS neurotransmitter
What type of receptors GABA A?
Inhibitory receptor
What are metabotropic receptors linked with?
Ion channel on plasma membrane
Through signal transduction pathway
What are metabotropic receptors more sensitive to?
Muscarine than nicotine
What is an example of a metabotropic receptor?
GABA B
= activates K+ channels
What are examples of ionotropic?
Nicotinic
GABA A
What are examples of metabotropic?
Muscarinic
GABA B
Describe G-protein receptors
All have 7 transmembrane domains
Activated by many molecules
Play role in regulation of cell function
What do G-coupled receptors consist of?
3 polypeptide chains Alpha, beta + gamma 16 alpha subunits 5 beta 11 gamma
What do beta + gamma subunits do in G-protein coupled receptors?
Bind tightly to each other
= beta-gamma subunit
What does alpha subunit bind to in G-protein coupled receptors?
Has guanine nucleotide binding site
= binds to GTP or GDP
What does alpha-GDP have a high affinity for?
Beta-gamma
What does alpha-GTP have a low affinity for?
Beta-gamma
What can alpha-subunit hydrolyse?
GTP
Where do the complexes of G-protein coupled receptors sit?
Inside plasma membrane
Describe G-protein cycle
Unstimulated cell
Adrenaline binding to beta-adrenoreceptor
Allows beta-adrenoreceptor/G-protein interaction
Allows GDP/GTP exchange
Allows alpha-subunit liberation
Free alpha subunit activates AC
Unbinding of adrenaline/GTP hydrolysis
What is PKA?
Protein Kinase A
Tetrameric protein with 2 types of polypeptide chain
Describe inactive PKA
Subunits bound together + R subunits suppresses activity of C subunit
What is the C + R subunit in PKA?
C = catalytic R = regulatory
What happens to make PKA active?
cAMP binds to dissociate
C subunit becomes active = phosphorylate other proteins
What does PKA do?
Catalyse transfer of ATP to specific serine/threonine residue on substrate proteins
What is the kidney collecting duct activated by?
Vasopressin + stimulates H2O retention
What is vascular smooth muscle + cardiac muscle activated by?
Adrenaline + promotes relaxation/increases HR
What is colonic epithelium activated by?
Various factors + promotes fluid/electrolyte secretion
What is the pancreas activated by?
By glucagon + promotes release of glucose in blood
Describe what happens in terminal signal transduction
cAMP hydrolysed by phosphodiesterase (PDE)
Hormone removed = PDE rapidly clears cAMP from cell
Unbinding of cAMP from R subunit
= increases affinity for C subunit
Protein reassembles into tetramer + inactivated
What are PDE’s inhibited by?
Caffeine
Describe desensitisation of receptor
Protein phosphorylation = cellular response
PKA phosphorylates beta-ARK + increases activity
beta-ARK phosphorylates beta-adrenoreceptors + reduces affinity for adrenaline
= reduced cellular response
What are the effects of kinase opposed by?
Protein phosphatases
What did the 1st G-protein contain?
Alpha subunit
= activates adenylyl cyclase (AC)
What did alpha-s subunit of G-protein do?
Activate AC
What did alpha-i subunit of G-protein do?
Inhibit AC
What are G-proteins a target for?
Bacterial toxins
What does the cholera toxin do to G-proteins?
Acts on alpha-s subunit + causes ADP-ribosylation
= prevents hydrolysis of GDP
= persistent activation of alpha subunit + PKA
What does the pertussis toxin do to G-proteins?
Act on alpha-i subunit = locks subunit into inactive configuration = prevention activation of receptors = prevents inhibitor control over AC/PKA = increased levels of cAMP + PKA
What do Gq proteins contain + why?
Alpha-q11 subunits
= allow hormones/neurotransmitters to activate amplifier enzyme
Describe Gq proteins 2nd messengers
Stimulate phospholipase C (PLC)
PLC cleaves PIP2 into inositol, 1,4,5-triphosphate (IP3) + diacylglycerol (DAG)
IP3 H2O soluble
= travels through cytosol to simulate Ca2+ release
DAG remains in membrane where it recruits protein kinase
What is IP3?
2nd messenger that stimulates Ca2+ release from ER
Describe IP3 function
Hydrophilic = enters through cytoplasm
Binds to receptors on ER = promotes release of Ca2+
Describe intracellular responses mediated by Ca2+
Each CaM binds to 4 Ca2+
Ca2+-CaM complex activates PDE + CaM kinases
CaMKs phosphorylates serine + threonine residues on no. of substrate proteins
What is CaM?
Calmodulin
What are CaMKs involved in?
Smooth-muscle contraction
What do alpha1-adrenoreceptor Gq-protein coupled receptors do?
Mediates vascular smooth muscle contraction by increasing intracellular free Ca2+, activating CaMKs
What are the effects of DAG?
Increases activity of Ca2+-dependent protein kinases
Evokes cellular response by phosphorylating other proteins
What is DAG + why is it important?
Hydrophobic
= remains in membrane
What can PKCs do?
Potentiate effects of IP3
What does alpha1-adrenoreceptor do to blood pressure?
Vasoconstriction
Via Gq-PLC-IP3
= increases BP
What does beta2-adrenoreceptors do to blood pressure?
Vasodilation
Via Gs-cAMP-PKA
= decreases BP
What are muscarinic receptors?
Gq/Gi coupled receptors
Describe receptor guanylyl cyclase
Contain 2 guanylyl cyclase domains
= convert GTP to cGMP
= activates downstream kinases
Describe the mechanism of signalling for receptor guanylyl cyclase
Binding of ANP induces conformational change in receptor = dimerization + activation
Guanylyl cyclase activity generates cGMP
Increased conc of cGMP = activates other signalling molecules
= determines response
Describe receptor serine/threonine kinases
Contain serine-threonine kinase domains
= phosphorylate target proteins
Describe mechanism of signalling for receptor serine/threonine kinases
1st messenger binds to receptor Type II
Receptor Type I binds forming ternary complex with Type II + 1st messenger
Type II receptor phosphorylates Type I = activating Ser-Thr kinase activity of Type I
Type I phosphorylates target protein
Describe receptor tyrosine kinases
Contain tyrosine kinase domains
= phosphorylate themselves/other proteins
Describe mechanism of action for receptor tyrosine kinases
Binding of 2 molecules of insulin = receptors dimerise
Use their cytoplasmic Tyr kinase activity to phosphorylate each other at multiple tyrosine residues
= “phosphotryosine motifs”
Recruit intracellular signalling molecules = response
Describe tyrosine kinase-associated receptors
DO NOT contain kinase domains
Instead associated non-covalently with cytoplasmic domains
Describe mechanism of action for tyrosine kinase-associated receptors
Binding of 1st messenger to receptor = conformational change = dimerization of receptor
= activation of associated Tyr kinases
= “phosphotryosine motifs”
= recruit intracellular signalling molecules = response
Describe receptor tyrosine phosphatases
Contain tyrosine phosphates domains
Dephosphorylate target proteins
Describe mechanism of action for receptor tyrosine phosphatases
CD45 binding to receptor = conformational change = activates Tyr phosphatases
= target proteins dephosphorylated
= regulation of downstream cell-signalling events
