G-Protein Coupled Receptors

G-Protein Coupled Receptors


G-PROTEIN COUPLED RECEPTORS

INTRODUCTION:

  • Large family of cell membrane receptors linked to effector.
  • To enzyme/channel/carrier protein).
  • Large heterotrimeric GTP-binding proteins (G proteins).
  • All have seven transmembrane segments.
  • Loops in & out of cell membrane.
  • (I.e.7 α-helical) membrane spanning.
  • Hormone binding site – Extracellular domain.
  • G-protein binding site – Intracellular domain.
STRUCTURE OF G-PROTEIN:
  • G-protein has three sub-units α, β & γ.
  • In inactive state, subunits form complex binding GDP on α-subunit.
On activation:

On extracellular ligand (hormone) binding Conformational change occur in receptor G-Protein activated.


GDP exchanged by GTP on α-subunit.

GDP displacement dissociates α-subunit from other two subunits.

Activated α-subunit carrying GTP induces intracellular signals.

Signal termination:

  • On hormone removal Signaling event terminated.
  • α-subunit inactivates itself by converting bound GTP to GDP.
  • Since α-subunit has GTPase activity.
  • α-subunit once again combines with β & γ subunits.
  • Forms inactive membrane-bound trimeric G protein.

TYPES OF Gα – SUBUNITS:

  • Action of active G protein – Either “Effector activation/inactivation”.
  • Because of different α-subunits (Gα subunits),
  • Gαs (Gs alpha) Stimulates adenylyl cyclase & ↑es cAMP.
  • Gαi (Gi alpha)Inhibits adenylyl ryclase & ↓es cAMP.
  • Gαq(Gq alpha)Activates phospholipase C (PLC) generating second messangers IP3 & DAG.
  • Gαt (Gt alpha)“t” – “Transducin” – Responsible for signal generation in retinal rods.

MECHANISM OF ACTION OF G-PROTEIN:

G protein activation acts in 2 ways – 

  • Stimulatory G protein – Stimulates; 
  • Inhibitory G protein – Inhibits.

1. Adenylyl cyclase (AC):

AC Activation –

  • Increases synthesis & intracellular accumulation of cAMP.
  • Due to stimulatory G protein action.
  • cAMP acts through cAMP-dependent Protein Kinase ‘A’.
  • In turn, phosphorylate & alters functions of many enzymes, ion channels & structural proteins.
  • Note: Inhibitory G protein inhibits AC & has opposite effects. 

Examples:

  • Corticotropin-releasing hormone (CRH), FSH, LH, TSH.
  • ACTH (corticotropin).
  • ADH (V2 receptors).
  • Parathormone.
  • Catecholamines (α2, β2) – Adrenaline (Most actions).
  • Glucagon.
  • hCG.
  • Calcitonin.
  • Somatostatin.
  • Acetylcholine.
  • Dopamine (D& D2).
  • Angiotensin II (epithelial cells).
  • GABAB.
  • Histamine (H2).

2. PHOSPHOLIPASE IP3 – DAG SYSTEM:

  • Phospholipase activation – By stimulatory G protein.
  • Hydrolyzes membrane phospholipid phosphatidylinositol 4, 5 bisphosphates (PIP2).
  • Generating second messenger “Inositol I, 4, 5 triphosphate” (IP3) & “Diacylglycerol” (DAG).
  • IP3 mobilizes Ca2+ from intracellular organelles → Increased cytosolic Ca2+.
  • DAG enhances Protein Kinase ‘C’ activation by Ca2+.
  • Ca2+ acts as “Third messenger” for this transduction mechanism.
  • Also mediates physiological effects of drugs.
  • Protein kinase-C phosphorylates various intracellular proteins.
  • Eg: Threonine, serine or tyrosine residue).
  • Causing their activation/inactivation.

Example:

  • Growth Hormone-Releasing Hormone (GHRH).
  • Thyrotropin-Releasing Hormone (TRH).
  • GnRH.
  • ADH/Vasopressin (V1 receptor – vasopressor action).
  • Oxytocin.
  • Cholecystokinin.
  • PDGF.
  • Gastrin.
  • Catecholamines (some actions via αreceptors).
  • Angiotensin II (vascular smooth muscle).
  • Substance P.
  • Histamine – H1.
  • Muscarinic (M& M3).

3. CHANNEL REGULATION:

  • Activated G-proteins can open/close ion channels – Ca2+, K+ or Na2+.

Examples:

  • Increased Ca2+1 adrenergic.
  • Decreased Ca2+-Dopamine D2
  • Increased K+-Adrenergic – α2.
  • Muscarinic M2.
  • Dopamine D2.
  • GABAB.

Exam Question

G-PROTEIN COUPLED RECEPTORS
  • G-protein has seven transmembrane segments.
  • (I.e.7 α-helical) membrane spanning.
  • Hormone binding site – Extracellular domain.
  • G protein activation results in exchange of GDP by GTP on α-subunit.
  • α-subunit dissociates from other two subunits.
  • α-subunit inactivates itself by converting its bound GTP to GDP, with help of GTPase activity.
  • Active G protein may either be effector activator/inactivator, because of different α-subunits (Gα – subunits).
  • Gαs (Gs alpha) → Stimulates adenylyl cyclase & ↑es cAMP.
  • Activation of AC results in increased synthesis & intracellular accumulation of cAMP.
  • cAMP acts through “cAMP-dependent Protein Kinase’A’ phosphorylates.

Examples: 

  • Corticotropin-releasing hormone (CRH).
  • FSH.
  • LH.
  • ACTH (corticotropin).
  • Catecholamines (α2, β2).
  • Glucagon.
  • Dopamine (D& D2).
  • Histamine (H2).
  • Phospholipase activation by stimulatory G protein hydrolyzes “Membrane Phospholipid Phosphatidylinositol 4, 5-Bisphosphates (PIP2), in turn, generating second messenger “Inositol I, 4, 5 triphosphate” (IP3) & “Diacylglycerol” (DAG).
  • Ca2+ acts as “Third messenger”.

Protein kinase-C phosphorylates various intracellular proteins.

  • Examples of IP-DAG system:
  • Cholecystokinin.
  • Catecholamines (some actions via αreceptors).
  • Histamine – H1.
 Examples of channel regulation:
  • Increased Ca2+1 adrenergic.
  • Increased K+-Adrenergic – α2.
Don’t Forget to Solve all the previous Year Question asked on G-Protein Coupled Receptors

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