deck_782667 Flashcards
What are G protein coupled receptors?
A family of receptors that act by altering the activity of effectors
What do G-proteins activate in order to interact with effectors?
Gunaine nucleotide binding proteins
What is the the word to describe G-proteins?
Heterotrimeric
How can G-proteins be described as heterotrimeric?
The consist of three different subunits - alpha, beta and gamma- Beta and gamma bind tightly together and form single unit- Alpha has a GTP binding site which has GTPase activity (slowly hydrolyses bound GTP to GDP)
Where is the G-protein usually present in the cell, and in what form?
at the inner face of the plasma membrane
Describe what occurs when G-protein coupled receptor binds an agonist
Agonist binds receptorProtein-Protein interaction releases GDP, binds GTP to alpha subunita-GTP and bg released and interact with effectorsGTP hydrolysed to GDPa-GDP and bg reform heterotrimer
What is the interaction of G proteins with effectors inhibited by?
Intrinsic GTPase activity of alpha subunit. Once bound GTP hydrolysed to GDP, the affinity of alpha subunit for bg increases, and the hetertotrimer reforms
How g proteins be thought of a switches and timers?
The on switch is receptor-facilitated GDP/GTP exchangethe timer/off switch is governed by the length of time taken for GTP hydrolysis.
What is the role of stimulatory G (Gs) proteins?
Plays an intermediate role - stimulate adenylyl cyclase to produce cAMP
What is the role of inhibitory G protein (Gi) paths?
Inhibit adenylyl cyclase, reducing cAMP Also effect ion channels and signalling pathways involved in growth and differntiation
What do Gq proteins interact with?
Activate phospholipase C, which hydrolyses PIP2 to IP3
What is the name of the light sensing receptor in the eye, and what does it activate?
Rhodopsin, activates Gt whichin turn activates a phosphodiesterase enzyme that hydrolyses cyclic GMP to 5’-GMP
What does adrenaline activate when activating b adrenoreceptors? Receptor, G protein, effects, physiological response
b-AdrenoceptorGsStimulates Adenylyl CyclaseGlycogenolysis, lipolysis
What does acetylcholine activate when interacting with M3?
GqStimulates Phospholipase CSmooth Muscle Contraction
What does Ach activate when interacting with M2?
GiInhibits Adenylyl CyclaseStimulates K+ ChannelSlowing of Cardiac Pacemaker
What does light do?
RhodopsinGtStimulates Cyclic GMP PhosphodiesteraseVisual Excitation
What G protein and effector do the following use?a1a2
a1 - Gq, stimulate phospholipase Ca2 - Gi, inhibit adenylyl cyclase
What G protein and effector do the following use?b1b2
b - Gs, stimulate adenylyl cylase
What G protein and effector do the following use?M1M2M3
M1 + M3 - Gq, stimulate phospholipase C,M2 - Gi, inhibit adenylyl cyclase
How many Ga, Gb and Gg exist?
20 Ga, 5Gb and 12+ Gg proteins.
How may possible Ga, Gb and Gg combinations are there?
over 1,000
How many receptor types are there, and what do they interact with?
800 receptor types, which can interact with different G subtypes to activate/inhibit 10 or more enzyme/ion channel effectors.
What do Cholera (CTx) and Petussis (PTx) toxin do the G protein cycle?
enzymes that ADP-Ribosylate specific G-Proteins
What does CTx do?
Eliminates the GTPase activity of Gsa, leading it to become irreversibly activated (opening chloride ion channels!)
What does PTx do?
PTx interferes with the GDP/GTP exchange on Gia. This leads Gia to become irreversibly inactivated.
What can genetic changes to GPCRs cause?
loss-of-function or gain-of-function mutations
How is retinitis Pigmentosa caused?
By a loss-of-function mutation to Rhodopsin
What are the symptoms of retinitis pigmentosa?
Severe visual impairment
How is nephrogenic diabetes insipidus cause?
By a loss-of-function mutation to V2 Vasopressin receptor
What are the symptoms of nephrogenic diabetes insipidus?
improper response of the kidney to ADH, leading to a decrease in the ability of the kidney to concentrate the urine by removing free water
What is Familial Male Precocious Puberty caused by?
a gain-of-function mutation (Receptor active without ligand) to the Luteinising Hormone (LH) Receptor
What are the symptoms of amilial Male Precocious Puberty?
Early onset puberty?
Name three diseases caused by mutations to G-protein coupled receptors
Retinitis Pigmentosa Nephrogenic Diabetes InsipidusFamilial Male Precocious Puberty
What is the mechanism of adenylyl cyclase?
This enzyme hydrolyses cellular ATP to generate cyclic AMP. Cyclic AMP interacts with a specific protein kinase (PKA) which phosphorylates a variety of proteins to affect cell activity
What does adenylyl cylcase cause to happen in cells?
-increased Glycogenolysis and gluconeogenesis in the liver- increased lipolysis in adipose tissue- relaxation of a variety of types of smooth muscle- positive inotropic and chronotropic effects in the heart.
What is the mechanism of phospholipase C?
Activates by Gq and hydrolses PIP2 to IP3IP3 exerts effects by interacting with receptors on ER to allow calcium to enter cytoplasm
How does Cyclic GMP phosphodiesterase work?
It regulates the breakdown of the second messenger cyclic GMP phosphodiesterase by Gt
How are G-protein coupled receptor pathways deactivated
- When activated, receptor vunerable to variety of protein kinases that phosphorylate the receptor and prevent it activating further G proteins- The active lifetime of a GTP may be limited by cellular factors that stimulate intrinsic GTPase activity of Ga subunit- Cells contain high activity enzymes that metabolise second messengers, rapidly returning their levels to the basal (favoured state)- Enzymatic cascades activated downstream of second messenger/protein kinase activation act to oppose their effect.
How is chronotrophy in the heart regulated?
- Rate at which SA node fires affect by Ach release by parasympathetic nerves- Activation of M2 receptors increases oen probability of K+ channels via Gi- Increasing membrane permeability to K+ causes hperpolarisation, slowing intrinsic firing rate- This causs negative chronotrophic effect
How is intotrophy in heart regulated?
- Sympathetic innervation of cardiac ventricles can influence force of contraction- Activation of B adreno receptors increases open probability of voltage operated calcium channels via Gs- Gs both interact directly with VOCCs and indirectly via cyclic AMP –> PKA –> phosphorylation and activation VOCCs- Influx of Ca2+ brings about postive inotropic effect
How is arteriolart vasoconstriction regulated?
Sympathetic release of noradrenaline acts on 1-adrenoceptors to stimulate phospholipase C and IP3 production via Gq. The IP3 releases ER Ca2+ (See above) and initiates a contractile response.
How is neutransmitter release modulated?
-Pre-synaptic G-Protein-Coupled Receptors - pre-synaptic u-opiod receptors can be stimulated, either by endogenous opiods or by analgesics such as morphine to couple to GaI proteins.- The G subunits liberated from the heterotrimer interact with VOCCs to reduce Ca2+ entry, thus reducing neurotransmitter release.
