metabotropic receptors Flashcards
what time frame do G-protein coupled receptors work in?s
seconds
what is an example of G-protein coupled receptors?
muscarinic ACh receptors
GPCR structure
- 7 transmembrane (TM) domains
- 3 intracellular, 3 extracellular loops
- N-terminus extracellular
- intracellular phosphorylation sites
- 3rd intracellular loop & C-terminus
interacts with G-protein - ligand binding in TM domains or
N-terminal domain - most are monomeric, some dimeric
sensory GPCR
rhodopsin
G-protein = GTPAse
when G-protien bound to GDP it is inactive however with stimulus it binds to GTP and forms active G-protien
intrisnic GTP activity= hydrolysis
heterotrimeric G-proteins
G-proteins that couple to GPCRs, the alpha subunit has GTPase activity, not the beta or gamma
the role of heterotrimeric G proteins in signal transduction
information transfer= signal to receptor to G protein to effectors
ligand bind to receptor which causes conformational change to G-protein can bind, GDP is exhanged for GTP (active)
alpha subunit and beta-gamma subunit diffuse apart and independently activate signalling pathways
alpha subunit will hydrolsyse into off state
what are 4 examples effector systems for G proteinsa
adenylate cyclase
phospholipase C
potassium channels
calcium channels
role of adenylate cyclase
catalyses the production of cyclic AMP (cAMP)
role of phopholipase C
catalyses the production of IP3 and diacyl glycerol (DAG) from PIP2
role of potassium channels
regulate membrane potential
role of calcium channels
allow calcium ions to enter the neuron
adenylate cyclase activity
- neurotransmitter binds to receptor
- activates G protein
- activates enzyme adenylate cyclase
- produces second messenger with cAMP
- cAMP activates protein kinase
- protein kinase phosphorylates K+ channel
phospholipase C activity
turns PIP2 into IP3 and DAG
these products are important second messengers
IP3 binds to calcium channels on the surface of ER= calcium flows out into cytosol which can activate calcium activated proteins (e.g protein kinase C that phosphorylates)
DAG also has to bind to protein kinase C to avtivate it
ion channel activity
alpha subunit binds to receptors
advantages of G proteins in signal transduction
- simple amplification
- signal diversification
signal amplification
a single receptor may activate several alpha-subunits
- epends on factors such as how long ligand remains bound
signal diversification
- receptors can interact with more than one type of G-protein
(there are >20 different variants of alpha-subunit) - G-proteins can regulate more than one effector
-eg. Gi and Go can inhibit adenylate cyclase, open K+ channels and close Ca2+-channels - Both alpha and beta-gamma subunits can regulate target proteins
3’,5’-Cyclic AMP (cAMP)
receptor= protein kinase A
action= protein phosphorylation
calcium ion
receptor= calmodulin and other calcium binding proteins
1,2-Diacylglycerol (DAG)
receptor= protein kinase C
action= protein phosphorylation
inositol 1,4,5-trisphosphate (IP3
receptor= Ca-release channel (IP3 receptor)
action= calcium release
presynaptic neuromodulation
- neuron releases 5HT, DA, Ach,
peptides, etc - GPCR activates effector system
- increased production of 2nd
messenger (e.g adenylate cyclase to cAMP) - intracellular “receptor” (eg protein
kinase) - phosphorylates K+ channel to close it
- VSCC allow Ca2+ into the presynaptic neuron
- glutamate is released
- glutamate receptors depolarise postsynaptic neuron
essentially through GPCR signalling you are effecting how active the presynapse is (more)
postsynaptic modulation (e.g cerebellar long term depression)
- presynaptic neuron releases glutamate
- mGluR activates effector system
- increased production of 2nd messengers
(DAG and IP3) - intracellular receptors (protein Kinase C and IP3
receptor) - PKC phosphorylates AMPA receptor
- IP3 receptor mediates Ca2+ release
- AMPAR phosphorylation plus other Ca2+- dependent processes cause AMPAR endocytosis
- this reduces synaptic strength
GPCR heterodimers
orginally dimers thought to be homodimers
however those working on GABAb receptors found them to be heterodimers, as a subunit on its own it doesnt work
this means there is a wide variety of heterodimeric G protein receptors
activation of heterodimer causes a different effect than its two subunits=expands receptor diversity signalling
