4.1 G-Protein Coupled Receptors (GPCRs)
GPCRs are the largest family of membrane receptors and represent ~34% of all FDA-approved drug targets. These seven-transmembrane domain receptors transduce extracellular signals through G-proteins to activate intracellular signaling cascades.
Structure and Mechanism
Seven Transmembrane Domains
GPCRs span the membrane seven times forming a characteristic structure:
- • Extracellular N-terminus (ligand binding site)
- • Seven α-helical transmembrane segments (TM1-TM7)
- • Three extracellular loops (ECL1-3)
- • Three intracellular loops (ICL1-3)
- • Intracellular C-terminus (G-protein coupling domain)
G-Protein Activation Cycle
1. Ligand binding → 2. Conformational change → 3. G-protein coupling → 4. GDP/GTP exchange → 5. G-protein dissociation (Gα-GTP + Gβγ) → 6. Effector activation → 7. GTP hydrolysis → 8. Reassociation
G-Protein Subtypes and Signaling
Gαs (Stimulatory)
Effector: Adenylyl cyclase ↑
Second messenger: cAMP ↑ → PKA activation
Examples: β-adrenergic receptors, D1 dopamine, H2 histamine, glucagon
Gαi/o (Inhibitory)
Effector: Adenylyl cyclase ↓
Second messenger: cAMP ↓
Examples: α2-adrenergic, M2/M4 muscarinic, D2 dopamine, opioid receptors (μ/δ/κ)
Gαq/11
Effector: Phospholipase C (PLC) ↑
Second messengers: IP3 (Ca²⁺ release) + DAG (PKC activation)
Examples: α1-adrenergic, M1/M3/M5 muscarinic, H1 histamine, angiotensin II
Gα12/13
Effector: Rho GEFs
Pathway: Rho/ROCK pathway
Effects: Cytoskeletal reorganization, smooth muscle contraction
Major GPCR Drug Classes
β-Adrenergic Agonists/Antagonists
Agonists: Albuterol (β2, asthma), isoproterenol (β1/β2) | Antagonists: Propranolol (β1/β2, hypertension), metoprolol (β1, heart failure)
Opioid Receptor Agonists
Morphine, fentanyl, oxycodone (μ-agonists, analgesia) | Naloxone (antagonist, overdose reversal)
Antihistamines
H1 antagonists: Diphenhydramine, loratadine (allergies) | H2 antagonists: Ranitidine (GERD)
Dopamine Modulators
D2 antagonists: Haloperidol, risperidone (antipsychotics) | D1/D2 agonists: Levodopa (Parkinson's)
Serotonin Modulators
5-HT1B/D agonists: Sumatriptan (migraines) | 5-HT2A antagonists: Atypical antipsychotics
Angiotensin Receptor Blockers (ARBs)
Losartan, valsartan (AT1 antagonists, hypertension)
GPCR Regulation
Desensitization
Rapid loss of response despite continued agonist presence. Mechanisms: 1) Receptor phosphorylation by GRKs (GPCR kinases) → 2) β-arrestin binding → 3) Receptor uncoupling from G-proteins
Internalization
Receptor endocytosis via clathrin-coated pits. β-arrestin serves as adaptor protein. Internalized receptors can be: 1) Recycled to membrane, or 2) Degraded in lysosomes
Downregulation
Chronic agonist exposure → decreased total receptor number. Mechanisms: Reduced transcription, increased degradation
Upregulation
Chronic antagonist use → increased receptor expression (supersensitivity). Clinical relevance: Rebound effects upon drug withdrawal
Clinical Significance
Why GPCRs are Druggable
- • Large, accessible ligand-binding pocket
- • High structural diversity → selective targeting possible
- • Modulate critical physiological processes
- • Both agonists and antagonists therapeutically useful
- • Biased agonism enables selective pathway activation
Therapeutic Areas
Cardiovascular (β-blockers, ARBs), CNS (antidepressants, antipsychotics, opioids), Respiratory (β2-agonists), GI (antiemetics), Endocrine (GLP-1 agonists), Oncology (CXCR4 antagonists)