True about G protein coupled receptors is -
Ans. Is 'c' i.e., G proteins act as inhibitory and excitatory because of difference in alpha subunito This question is repeat from AIIMS May 08.o Ligand (hormone) binding site of G-protein coupled receptor (GPCR) is on the outer surface of cell membrane and G protein binding site is intracellular. G protein does not bind to hormone on the surface of cell,o G-protein has three subunits, the a, b and g subunits. For action of G-protein, only active a-subunit is required and on activation p and y subunits dissociate from a-subunit.o G-protein can acts as inhibitory as well as excitatory because of difference in alpha subunits. For example, Gas stimulates adenylyl cyclase, whereas Gai inhibits adenylyl cyclase.o GTP bind to G-protein in active state.G-protein coupled receptorso These are large family of cell membrane receptors which are linked to effector (enzyme/channel/carrier protein ) through G proteins for response effectuation. These are large heterotrimeric GTP-binding proteins (G proteins). All have seven transmembrane segments that loop in and out of the cell membrane, i.e., 7 a-helical membrane spanning. The hormone binding site is an extracellular domain. G-protein binding site is intracellular.o G-protein has three subunits a, b and g. In their inactive state, the a, b and g subunits of G-proteins form a complex that binds GDP on a- subunit. When the ligand (hormone) binds to the extracellular part of the receptor, a conformational change occurs in the receptor that activates the G proteins. This results in exchange of GDP by GTP on a-subunit. Displacement of GDP by GTP causes the a-subunit to dissociate from the other two subunits. The activated a-subunit carrying GTP induces intracellular signals (mechanism will be discussed later).o The signaling event is terminated when the hormone is removed and the a-subunit inactivates itself by converting its bound GTP to GDP as a-subunit has GTPase activity . Then the a-subunit once again combines with the b and gsubunits to form an inactive membrane bound trimeric G protein.o The action of active G protein may be either activation or inactivation of the effector. This is because of different a-subunits (Ga subunits).# Gas (Gs alfa) - Stimulates adenylyl cyclase and increases cAMP.# Gai (Gi alfa) - Inhibits adenylyl cyclase and decreases cAMP.# Gaq (Gq alfa) - Activates phospholipase C (PLC) which generates second messangers IP3 and DAG.# Gat (Gt alfa) - The "t" is for transducin, the molecule responsible for generating a signal in the rods of the retina.Mechanism of action# This activated G protein effects one of the following effect pathway (activated stimulatory G protein stimulates, or activated inhibitory- G protein inhibits) - A) Adenylyl cyclase (AC)o Activation of AC results in increased synthesis and intracellular accumulation of cAMP (by stimulatory G protein). cAMP acts through cAMP dependent Protein Kinase ' A', which phosphorylate and alters the function of many enzymes, ion channels and structural proteins. Inhibitory G protein inhibits AC and has opposite effects.o Examples - Corticotropin releasing hormone (CRH), FSH, LH, TSH, ACTH (corticotropin), ADH, Vasopressin (V2 receptors), Parathormone, Catecholamines (b,a2) e.g., adrenaline (most actions), Glucagon, hCG, Calcitonin, Somatostatin, acetylcholine (M2), Dopamine (D1, D2), Angiotensin II (epithelial cells), GABAB, Histamine (H2).B) Phospholipase IP3-DAG systemo Activation of phospholipase (by stimulatory G protein) hydrolyses the membrane phospholipid phosphatidyl inositol 4, 5 bisphosphate (PIP2) to generate the second messenger inositol 1, 4, 5 - triphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes Ca+2 from intracellular organelles - increased cytosolic Ca+2. DAG enhances Protein Kinase 'c' activation by Ca+2. Ca+1 acts as third messenger in this type of transduction mechanism and mediates the physiological effects of drugs,o Example - Growth hormone releasing hormone (GHRH), Thyrotropin releasing hormone (TRH), GnRh, ADH/Vasopressin (VI receptor; vasopressor action), oxytocin, cholecystokinin, PDGF, Gastrin, Catecholamines (some actions via a1, receptors), Angiotensin II (vascular smooth muscle), Substance P, Histamine - H1, muscarinic M1, M3C) Channel regulationo Activated G-proteins can open or close ion channels - Ca+, K+ or Na+.o Examples - (1) | Ca+2-b1-adrenergic, (2) -l Ca+2-Dopamine D2, GABAB, (3) | K+ -Adrenergic -a2, muscarinic M2, Dopamine D2, GABAB.
G proteins bind to hormones on the cell surface
All the three subunits alpha, beta and gamma should bind to each other for G protein to act
G proteins act as inhibitory and excitatory because of difference in alpha subunit
G protein is bound to GTP in resting state
Chemical Messengers: Receptors