Lecture 10 Flashcards
Structure of G-protein coupled receptor
- 7 transmembrane alpha helical subunits (H1-7)
- G-protein interact with a-helices 5 and 6 (C3)
NH3+ E1, C1, E2, C2 etc for bonds
Process of cell signalling
- Signal
- Perception
- Transduction
- Response
Explain what comes under the 3 principal groups of G-protein coupled receptors
Family A - Biological amines, Light or odorants, Peptides or chemokines, Purines, Lipids
Family B - Peptides
Family C - Biological amines, Glutamate, Ca2+
5 examples of biological functions mediated by 7TM receptors
Hormone action and secretion
Chemotaxis
Exocytosis
Senses e.g. taste, smell, vision
Embryogenesis
5 important human G-protein coupled receptors
Histamine H2 receptor - Acid secreting cells of stomach - stimulates acid secretion
Histamine H1 receptor - Smooth muscle, vascular epithelial cell - Increases vascular permeability and symptoms of allergies
Serotonin 5HT2A - Central nervous system - Synaptic transmission between neurons
Serotonin HTA1A - Central nervous system - Synaptic transmission between neurons
Angiotensin AT1 - Vascular smooth muscle cells - Constricts blood vessels, increasing blood pressure
What drugs treat the 5 G protein types
Histamine H2 receptor - Cimetidine and Ranitidine - Prevent acid stomach, treats stomach ulcers
Histamine H1 receptor - Fexofenadine and Loratadine - reduce allergy symptoms
Serotonin 5HT2A - clozapine, risperidone - treat schizophrenia
Serotonin 5HT1A - Buspirone - Treat depression and anxiety
Angiotensin AT1 - Reduce hypertension by losartan
Explain epinephrine
Hormome that binds Beta-adrenergic receptor
Fight or flight hormone - Catecholamine, adrenal glands (adrenal medula)
Increases glycogen breakdown
Increases release of fatty acids
cAMP pathway
Epinephrine binds to Beta adrenergic receptor, activating the receptor
GTP is exchanged for GDP in amplification to activate the G protein
GTP form of alpha subunit binds to adenylate cyclase which cause ATP to be converted into cAMP
Rising levels of cAMP activates protein kinase A
How many amino acids does epinephrine interact with on beta adrenergic receptor?
15 amino acids on 4 transmembrane alpha helices
G protein cycle
ON –> H2O->Pi and addition of By to alpha GDP subunit –> OFF
OFF –> GTP hydrolysis and removal of By subunit –> ON
Adenylate cyclase
2 catalytic domains
1 catalytic domain attaches 2 components each containing 6 transmembrane a helical subunits
What do Ga subunits have?
Intrinisic GTPase activity
adenylate cyclase-GTP Gas –> H2O->Pi –> adenylate cyclase-GDP Gas –> adenylate cyclase + Heterotrimeric G protein
Signal termination
- Dissociation
- Phosphorylation by GPCR kinase + binding of arrestin
- Endocytosis
How many different Ga subunits are there
Over 20
What is the stimulatory Ga subunit
Gas
Associated effector: adenylyl cyclase
Secondary messenger: cAMP (increased)
What is the inhibitory Ga subunit
Gai
Associated effector: Adenylyl cyclase K+ channel (GBy activates effecctor)
Secondary messenger: cAMP (decreased), Change in membrane potential
What is the olfactory Ga subunit
Gaolf
Associated effector: Adenylyl cyclase
Secondary messenger: cAMP (increased)
What is the visual Ga subunit?
Gat
Associated effector: cGMP phosphodiesterase
Secondary messenger: cGMP (decreased)
How is cAMP regulated?
Stimulatory (Epinephrine glucagon ACTH) and inhibitory (PFE1 adenosine) hormones bind receptor
Activates heterotrimeric G proteins including Gas or Gai
GTP form of Gas or Gai bind adenylyl cyclase, activating or inhibiting production of cAMP
What occurs when PIP2 is cleaved by phospholipase C?
- Activates PKC (initiating kinase cascade)
- Releases Ca2+ from intracellular stores
Role of IP3 and DAG
IP3 and DAG are released from phospholipase C
IP3 binds to IP3-gated calcium ion channels to allow calcium ion release from endoplasmic reticulum
DAG binds to PKC (initiating kinase cascade) to allow for phosphorylation of substrates
