g protein coupled reaction. Pharmacology
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That's a nicotinic receptor image (ligand-gated ion channel), not a GPCR diagram. I have all the material needed now. Let me compile the comprehensive answer.
G Protein-Coupled Receptors (GPCRs) - Pharmacology
1. Overview
GPCRs are the largest family of cell surface receptors in the human genome (>800 members). They mediate responses to hormones, neurotransmitters, odorants, and photons, and are targets for approximately 30-40% of all approved drugs.
They are also called:
- Seven-transmembrane (7-TM) receptors - because the polypeptide chain crosses the membrane 7 times
- Serpentine receptors - because of their winding structure across the membrane
Katzung's Basic and Clinical Pharmacology, 16th Edition - The receptor polypeptide chain "snakes" across the plasma membrane seven times. Agonist binds from the extracellular side; the G protein interacts with cytoplasmic regions, especially the third cytoplasmic loop connecting transmembrane regions V and VI.
2. Structure of a GPCR
- Extracellular N-terminus - ligand binding domain
- 7 hydrophobic transmembrane helices (I-VII) - embedded in the lipid bilayer
- 3 extracellular loops and 3 intracellular loops
- Intracellular C-terminus - couples to G proteins
The G protein heterotrimer has 3 subunits:
- Gα - binds GTP/GDP; determines effector specificity
- Gβ and Gγ - anchor the complex to the cytoplasmic membrane face; also have independent signaling roles
3. The Activation Cycle (GTP-GDP Cycle)
This is the core mechanism - illustrated below:
Step-by-step:
| Step | Event |
|---|---|
| 1. Basal state | Receptor is unoccupied. Gα subunit is bound to GDP; heterotrimer (αβγ) is inactive. |
| 2. Agonist binds | Agonist binds receptor → receptor undergoes conformational change → receptor acts as a guanine nucleotide exchange factor (GEF) |
| 3. GDP → GTP exchange | Activated receptor promotes release of GDP from Gα; GTP (abundant in cytoplasm) enters the nucleotide binding site |
| 4. Dissociation | GTP-bound Gα dissociates from Gβγ; both GTP-Gα and free Gβγ can now activate downstream effectors |
| 5. Effector activation | GTP-Gα (or Gβγ) activates enzymes (adenylyl cyclase, PLC) or ion channels |
| 6. Signal termination | Gα has intrinsic GTPase activity → hydrolyzes GTP to GDP → Gα becomes inactive again → reassociates with Gβγ → cycle resets |
Katzung's, p. 57: "GTP-bound Gs may remain active for tens of seconds before it is inactivated by hydrolysis, prolonging and enormously amplifying the original signal."
4. G Protein Subtypes and Their Effectors
| G Protein | Receptors (Examples) | Effector | Effect |
|---|---|---|---|
| Gs | β-adrenoceptors, glucagon-R, TSH-R, D1/D5 dopamine, 5-HT4 | ↑ Adenylyl cyclase | ↑ cAMP |
| Gi | α2-adrenoceptors, muscarinic M2/M4, opioid receptors, D2 dopamine | ↓ Adenylyl cyclase; open K+ channels | ↓ cAMP; ↓ heart rate |
| Gq | Muscarinic M1/M3, α1-adrenoceptors, 5-HT2, histamine H1 | ↑ Phospholipase C-β | ↑ IP3 + DAG → ↑ Ca2+ + PKC |
| Golf | Odorant receptors (olfactory epithelium) | ↑ Adenylyl cyclase | ↑ cAMP |
| Gt (Transducin) | Rhodopsin, color opsins (retinal rods/cones) | ↑ cGMP phosphodiesterase | ↓ cGMP (phototransduction) |
| G12/13 | Thromboxane, LPA receptors | Rho-GEF | Cytoskeletal changes |
Source: Katzung's Basic and Clinical Pharmacology, Table 2-1
5. Second Messenger Pathways
Pathway A: cAMP (via Gs or Gi)
Gs → ↑ adenylyl cyclase → ATP → cAMP → ↑ Protein Kinase A (PKA)
PKA phosphorylates target proteins, producing effects like:
- Cardiac: ↑ heart rate and contractility (β1 adrenoceptor)
- Smooth muscle: relaxation (β2 adrenoceptor)
- Metabolic: glycogenolysis (glucagon receptor)
Gi → ↓ adenylyl cyclase → ↓ cAMP → ↓ PKA (opposite effects)
Pathway B: IP3/DAG/Ca²+ (via Gq)
Gq → ↑ Phospholipase C-β (PLC-β) → cleaves PIP2 into IP3 + DAG
- IP3 (inositol-1,4,5-trisphosphate): diffuses to ER/sarcoplasmic reticulum → releases Ca²+ into cytoplasm → Ca²+ binds calmodulin → activates calmodulin-dependent kinases (e.g., myosin light chain kinase - smooth muscle contraction)
- DAG (diacylglycerol): stays in membrane → activates Protein Kinase C (PKC) → phosphorylates various substrates
Lippincott Illustrated Reviews: Pharmacology: "DAG and cAMP activate specific protein kinases within the cell, leading to a myriad of physiological effects. IP3 increases intracellular calcium concentration, which in turn activates other protein kinases."
Termination:
- IP3 is dephosphorylated (lithium inhibits this step - relevant to bipolar disorder treatment)
- DAG is phosphorylated to phosphatidic acid or deacylated to arachidonic acid
- Ca²+ is actively pumped out by Ca²+ pumps
Pathway C: cGMP
Relevant in:
- Retina: rhodopsin (GPCR for light) → Gt (transducin) → ↑ cGMP phosphodiesterase → ↓ cGMP → closure of cGMP-gated Na+ channels → hyperpolarization → visual signal
- Vascular smooth muscle: NO → guanylyl cyclase → ↑ cGMP → ↑ PKG → myosin dephosphorylation → vasodilation (basis for sildenafil's action - PDE5 inhibitor prevents cGMP breakdown)
6. Key Pharmacological Concepts
Signal Amplification
One agonist-receptor complex can activate many G proteins; each active adenylyl cyclase molecule generates many cAMP molecules - this creates a cascade amplification effect.
Desensitization (Tachyphylaxis)
Prolonged agonist exposure causes:
- GPCR kinases (GRKs) phosphorylate the activated receptor
- β-arrestin binds the phosphorylated receptor → sterically uncouples G protein
- Receptor internalization (endocytosis) - reduces surface receptor density
Biased Agonism (Functional Selectivity)
Most GPCRs can signal through both G protein and β-arrestin pathways. Some drugs preferentially activate one pathway - e.g., G protein-biased opioid agonists (aim: analgesia without β-arrestin-mediated side effects).
Kaplan & Sadock's: "Classical receptor pharmacology theory posits that a full agonist at a receptor will activate all signaling pathways equally... [but] biased agonism describes drugs that selectively activate one pathway over another."
7. Clinically Important GPCRs and Drugs
| Receptor | Drugs Acting on It | Indication |
|---|---|---|
| β1/β2-adrenoceptor (Gs) | Salbutamol (agonist), Propranolol (antagonist) | Asthma, hypertension, heart failure |
| α1-adrenoceptor (Gq) | Prazosin (antagonist) | Hypertension, BPH |
| α2-adrenoceptor (Gi) | Clonidine (agonist) | Hypertension, ADHD |
| Muscarinic M1/M3 (Gq) | Atropine (antagonist), Pilocarpine (agonist) | Glaucoma, dry secretions |
| Muscarinic M2 (Gi) | Atropine | Bradycardia |
| Opioid μ-receptor (Gi) | Morphine, Fentanyl | Pain |
| D2 dopamine (Gi) | Haloperidol (antagonist) | Psychosis |
| H1 histamine (Gq) | Diphenhydramine (antagonist) | Allergies |
| 5-HT2 serotonin (Gq) | Clozapine (antagonist) | Atypical antipsychotic |
| Glucagon-R (Gs) | Glucagon, Semaglutide (GLP-1R) | Hypoglycemia, diabetes/obesity |
8. Toxins That Exploit the GPCR System
| Toxin | Mechanism | Effect |
|---|---|---|
| Cholera toxin | ADP-ribosylates Gsα → locks GTP in place (prevents GTPase) | Constitutive ↑ cAMP in intestinal cells → massive Cl-/water secretion → watery diarrhea |
| Pertussis toxin | ADP-ribosylates Giα → prevents receptor coupling | ↑ cAMP (blocks Gi suppression) → whooping cough pathology |
Sources: Katzung's Basic and Clinical Pharmacology (16th ed.), Lippincott Illustrated Reviews: Pharmacology, Goodman & Gilman's The Pharmacological Basis of Therapeutics, Costanzo Physiology (7th ed.)
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