U01.05.017 G-protein–linked second messengers

G-protein–linked receptors are integral to a wide range of physiological processes. They are involved in mediating the effects of various signaling molecules by activating G-proteins, which then influence second messengers inside the cell. These second messengers trigger cascades of intracellular events that regulate cellular function.

Key Classes of GPCRs and Their Functions

1. Adrenergic Receptors

α1 (Gq)
- Functions:
  - Vasoconstriction (vascular smooth muscle contraction)
  - Mydriasis (pupillary dilator muscle contraction)
  - Sphincter muscle contraction (intestinal, bladder)
α2 (Gi)
- Functions:
  - Inhibition of sympathetic outflow
  - Inhibition of insulin release
  - Platelet aggregation
  - Decreased aqueous humor production
β1 (Gs)
- Functions:
  - Increased heart rate and contractility
  - Renin release
  - Lipolysis
β2 (Gs)
- Functions:
  - Vasodilation and bronchodilation
  - Lipolysis, insulin release
  - Glycogenolysis
  - Uterine relaxation (tocolysis)
  - Aqueous humor production
  - Cellular potassium uptake
β3 (Gs)
- Functions:
  - Lipolysis
  - Thermogenesis in skeletal muscle
  - Bladder relaxation

2. Cholinergic Receptors

M1 (Gq)
- Functions:
  - Cognitive functions (higher functions)
  - Stimulates the enteric nervous system
M2 (Gi)
- Functions:
  - Decreased heart rate
  - Reduced contractility in atria
M3 (Gq)
- Functions:
  - Exocrine gland secretion (lacrimal, sweat, salivary, gastric acid)
  - Gut peristalsis
  - Bladder contraction
  - Bronchoconstriction
  - Pupillary sphincter contraction (miosis)
  - Ciliary muscle contraction (accommodation)
  - Insulin release
  - Endothelium-mediated vasodilation

3. Dopamine Receptors

D1 (Gs)
- Functions:
  - Relaxation of renal vascular smooth muscle
  - Activation of direct pathway in striatum
D2 (Gi)
- Functions:
  - Modulation of neurotransmitter release in the brain
  - Inhibition of indirect pathway in striatum

4. Histamine Receptors

H1 (Gq)
- Functions:
  - Increased nasal and bronchial mucus production
  - Vascular permeability
  - Bronchoconstriction
  - Pruritus (itching)
  - Pain
H2 (Gs)
- Functions:
  - Gastric acid secretion

5. Vasopressin Receptors

V1 (Gq)
- Functions:
  - Vascular smooth muscle contraction
V2 (Gs)
- Functions:
  - Increased water permeability and reabsorption (via aquaporin-2)
  - Release of Von Willebrand factor (vWF)

Summary Table: Receptors and Their Second Messengers

Receptor Class	G-Protein	Major Functions
Adrenergic (α1)	Gq	Vasoconstriction, mydriasis, sphincter contraction
Adrenergic (α2)	Gi	Inhibit sympathetic outflow, inhibit insulin release, platelet aggregation, reduce aqueous humor production
Adrenergic (β1)	Gs	Increased heart rate, contractility, renin release, lipolysis
Adrenergic (β2)	Gs	Vasodilation, bronchodilation, lipolysis, glycogenolysis, uterine relaxation, aqueous humor production
Adrenergic (β3)	Gs	Lipolysis, thermogenesis, bladder relaxation
Cholinergic (M1)	Gq	Cognitive functions, stimulates enteric nervous system
Cholinergic (M2)	Gi	Decreased heart rate, reduced atrial contractility
Cholinergic (M3)	Gq	Glandular secretion, gut peristalsis, bladder contraction, bronchoconstriction, insulin release, vasodilation
Dopamine (D1)	Gs	Renal smooth muscle relaxation, activates striatal direct pathway
Dopamine (D2)	Gi	Modulates transmitter release, inhibits striatal indirect pathway
Histamine (H1)	Gq	Increased mucus production, vascular permeability, pruritus, bronchoconstriction, pain
Histamine (H2)	Gs	Gastric acid secretion
Vasopressin (V1)	Gq	Vascular smooth muscle contraction
Vasopressin (V2)	Gs	Increased water reabsorption (kidney), release of vWF

Key Mnemonics for USMLE Step 1

“After qisses (kisses), you get a qiq (kick) out of siq (sick) sqs (super qinky sex).”
This mnemonic helps to remember the receptor-G-protein coupling: q = Gq, i = Gi, s = Gs.
HAVe 1 M&M for remembering GPCR classes:
- H for Histamine
- A for Adrenergic
- V for Vasopressin
- M for Muscarinic (Cholinergic)
- 1 for Class 1 (Gq)
- M&M for Muscarinic receptors M1, M2, and M3
“People who are too (2) MAD inhibit themselves.”
- M = M2, A = D2, D = Dopamine receptors (Gi).

Points to Remember

Gq Pathway: Involves IP3 and DAG, leading to increased intracellular calcium and activation of protein kinase C (PKC).
Gs Pathway: Leads to activation of adenylate cyclase, increasing cAMP, and activation of protein kinase A (PKA).
Gi Pathway: Inhibits adenylate cyclase and reduces cAMP production, leading to decreased cellular activity.

USMLE Step 1 Review Series

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