Drug-Receptor Interactions
Pharmacology · General Pharmacology · lean revision notes
Drug-Receptor Interactions
Receptors are the macromolecular targets through which most drugs produce their effects. For NEET PG, the receptor superfamilies, their second-messenger cascades, signalling speed, and the prototype drugs acting on each are recurringly tested — usually as "match-the-receptor" or "predict-the-downstream-effect" questions.
1. Definition & basic concepts
A receptor is a regulatory macromolecule (usually a protein) to which a drug or endogenous ligand binds and thereby alters cell function. The drug-receptor interaction is the basis of pharmacodynamics ("what the drug does to the body").
Key working definitions:
- Agonist — binds and activates the receptor (has affinity + intrinsic activity = 1).
- Partial agonist — binds but produces a sub-maximal response even at full occupancy (intrinsic activity between 0 and 1); acts as an agonist when alone, but as an antagonist in the presence of a full agonist (e.g. pindolol, buprenorphine, aripiprazole).
- Inverse agonist — produces an effect opposite to the agonist by stabilising the inactive receptor state; needs constitutive (basal) receptor activity (e.g. some β-carbolines at GABA-A, anti-histamines as inverse agonists at H1).
- Antagonist — has affinity but zero intrinsic activity; blocks the agonist.
- Affinity — capacity to bind (reflected by Kd; lower Kd = higher affinity).
- Efficacy / intrinsic activity — capacity to activate once bound.
- Potency — dose required to produce a given effect (reflected by ED50/EC50).
High-yield: Affinity is shown on the x-axis (potency, EC50) of a dose-response curve; efficacy is the y-axis maximal response (Emax). A more potent drug sits to the left; a more efficacious drug reaches a higher plateau.
Spare receptors
When maximal response is reached while a fraction of receptors remain unoccupied, the surplus are spare receptors. Their presence increases sensitivity (lowers EC50), so a full agonist can produce Emax with low occupancy. Spare receptors are classically demonstrated with irreversible antagonists — low doses merely shift the curve right (because spares are recruited) before reducing Emax.
2. Classification of receptors (the four superfamilies)
This is the single most-tested table in general pharmacology. Memorise the prototype, transduction mechanism, and time scale.
| Superfamily | Structure | Signal transducer | Time scale | Prototype ligands |
|---|---|---|---|---|
| Ligand-gated ion channel (ionotropic) | Multi-subunit channel spanning membrane | Direct ion flux (Na⁺, K⁺, Ca²⁺, Cl⁻) | Milliseconds | Nicotinic ACh (Nm/Nn), GABA-A, glycine, NMDA/AMPA, 5-HT₃ |
| G-protein coupled receptor (GPCR, metabotropic, 7-TM serpentine) | Single peptide, 7 transmembrane domains | G-protein → second messenger (cAMP, IP₃/DAG, Ca²⁺) | Seconds | Adrenergic, muscarinic, dopaminergic, opioid, most peptide hormones |
| Enzyme-linked (catalytic) receptor | Single TM domain; intrinsic or associated enzyme | Tyrosine kinase / guanylyl cyclase / Ser-Thr kinase / JAK-STAT | Minutes | Insulin, EGF, growth factors, ANP, cytokines, GH, leptin |
| Nuclear (intracellular) receptor | Cytoplasmic/nuclear, DNA-binding | Altered gene transcription (mRNA → protein) | Hours | Steroids, thyroxine, vitamin D, retinoids, PPAR |
High-yield: Order of speed — Ion channel (ms) → GPCR (s) → Enzyme-linked (min) → Nuclear (hours). The slowest receptor family (nuclear) gives the longest-lasting effects, explaining the delayed onset and prolonged duration of steroids and thyroxine.
Mnemonic for receptor speed: "Channels are quick, Genes are slow" — ionotropic fastest, transcription slowest.
3. G-protein coupled receptors & second messengers (HIGHEST yield)
GPCRs couple to heterotrimeric G-proteins (α, β, γ). On agonist binding, GDP on Gα is exchanged for GTP, the Gα-GTP dissociates from βγ, and both regulate effectors. Intrinsic GTPase activity terminates the signal.
| G-protein | Effector | Second messenger | Net effect | Key receptors |
|---|---|---|---|---|
| Gs | ↑ Adenylyl cyclase | ↑ cAMP → PKA | Excitatory metabolic | β₁, β₂, β₃, D₁, H₂, glucagon, 5-HT₄, V₂ |
| Gi/Go | ↓ Adenylyl cyclase (Gi); ↓ Ca²⁺/↑ K⁺ channels (Go) | ↓ cAMP | Inhibitory | α₂, M₂, M₄, D₂, μ/δ/κ opioid, 5-HT₁, GABA-B, A₁ adenosine |
| Gq | ↑ Phospholipase C-β | ↑ IP₃ + DAG → Ca²⁺ & PKC | Excitatory, contractile/secretory | α₁, M₁, M₃, M₅, H₁, V₁, 5-HT₂, AT₁, TXA₂ |
The cAMP pathway (Gs / Gi)
Gs → adenylyl cyclase → ATP converted to cAMP → activates protein kinase A (PKA) → phosphorylates target proteins. cAMP is degraded by phosphodiesterase (PDE).
High-yield: Methylxanthines (theophylline, caffeine) inhibit PDE → ↑ cAMP. Forskolin directly activates adenylyl cyclase. Cholera toxin ADP-ribosylates Gs (locks it ON → persistent ↑cAMP → watery diarrhoea). Pertussis toxin ADP-ribosylates Gi (locks it OFF → unopposed ↑cAMP).
The IP₃/DAG pathway (Gq)
Gq → phospholipase C-β cleaves membrane PIP₂ into:
- IP₃ (inositol trisphosphate) → binds ER receptor → releases intracellular Ca²⁺.
- DAG (diacylglycerol) → activates protein kinase C (PKC) (membrane-bound).
The rise in cytosolic Ca²⁺ + PKC drives smooth-muscle contraction, glandular secretion and platelet aggregation.
Flow of α₁ activation: Noradrenaline → α₁ receptor → Gq → PLC-β → PIP₂ → IP₃ + DAG → IP₃ releases Ca²⁺ from ER; DAG activates PKC → vascular smooth-muscle contraction → vasoconstriction → ↑BP.
High-yield: β receptors → Gs → ↑cAMP (heart stimulation, bronchodilation, glycogenolysis). α₂ → Gi → ↓cAMP (presynaptic ↓NA release, central sympatholysis — clonidine). α₁ → Gq → IP₃/DAG (vasoconstriction, mydriasis). Knowing α₂ is Gi (NOT Gq) is a classic distractor.
4. Ligand-gated ion channels (ionotropic)
Fastest signalling — the receptor is the channel. Subunit composition decides the permeant ion.
| Receptor | Ion | Net effect | Drugs / notes |
|---|---|---|---|
| Nicotinic (Nm – muscle) | Na⁺/K⁺ in | Depolarisation, contraction | Blocked by tubocurarine; activated by ACh, succinylcholine |
| Nicotinic (Nn – ganglion/CNS) | Na⁺/K⁺ | Ganglionic transmission | Hexamethonium (blocker), nicotine |
| GABA-A | Cl⁻ influx | Hyperpolarisation (inhibitory) | Benzodiazepines ↑frequency, barbiturates ↑duration of Cl⁻ channel opening |
| Glycine | Cl⁻ | Inhibitory (spinal cord) | Blocked by strychnine; tetanus toxin inhibits release |
| NMDA / AMPA | Na⁺, Ca²⁺ | Excitatory (glutamate) | Ketamine, memantine block NMDA |
| 5-HT₃ | Na⁺/K⁺ | Excitatory | Ondansetron blocks (antiemetic) |
High-yield: GABA-A and glycine are the two major inhibitory chloride channels. GABA-B, in contrast, is a GPCR (Gi) — baclofen acts here. Distinguishing GABA-A (ionotropic Cl⁻) from GABA-B (metabotropic K⁺/Ca²⁺) is a frequent question.
Benzodiazepine vs barbiturate at GABA-A: "Frequs Ben, Durab Barb" — Benzodiazepines increase frequency of channel opening; Barbiturates increase duration.
5. Enzyme-linked receptors
Single transmembrane span; the cytoplasmic tail carries (or recruits) enzyme activity.
- Receptor tyrosine kinase (RTK): Ligand → dimerisation → autophosphorylation of tyrosine residues → RAS-MAP kinase & PI3K-Akt cascades. Examples: insulin, EGF, PDGF, VEGF, FGF. Insulin receptor is a pre-formed (α₂β₂) tetramer joined by disulphide bonds.
- JAK-STAT (cytokine receptors): No intrinsic kinase; associated Janus kinase (JAK) phosphorylates STAT, which dimerises and migrates to the nucleus. Examples: growth hormone, prolactin, erythropoietin, leptin, interferons, many interleukins. Drug link: tofacitinib, ruxolitinib are JAK inhibitors.
- Receptor guanylyl cyclase: Ligand → ↑ cGMP → protein kinase G. Example: ANP/BNP (membrane-bound GC). Note: NO and nitrates act on soluble (cytoplasmic) guanylyl cyclase → ↑cGMP → vasodilation; sildenafil ↑cGMP by inhibiting PDE-5.
- Receptor serine/threonine kinase: TGF-β family.
High-yield: Insulin = receptor tyrosine kinase. Growth hormone, prolactin, EPO, leptin, interferons = JAK-STAT. ANP = membrane guanylyl cyclase (↑cGMP). These three are perennial MCQ stems.
6. Nuclear (intracellular) receptors
Lipophilic ligands cross the membrane and bind cytoplasmic/nuclear receptors that act as ligand-activated transcription factors.
- Type I (cytoplasmic): Steroid receptors (glucocorticoid, mineralocorticoid, androgen, oestrogen, progesterone). Bound to HSP90 when inactive; ligand binding releases HSP → homodimer → migrates to nucleus → binds hormone-response element (HRE).
- Type II (nuclear, already on DNA): Thyroid hormone (T3), vitamin D, retinoic acid (RAR/RXR), PPAR. Usually heterodimerise with RXR.
Effect: altered transcription → new mRNA → new protein. This explains the characteristic lag of hours and prolonged action.
High-yield: Steroids and thyroxine have a slow onset and long duration because they work via gene transcription. Thiazolidinediones (pioglitazone) act on PPAR-γ; fibrates on PPAR-α.
7. Quantitative pharmacodynamics — antagonism
| Feature | Competitive (reversible) | Non-competitive / irreversible |
|---|---|---|
| Binding site | Same as agonist (orthosteric) | Different site, or covalent at active site |
| Effect on agonist curve | Parallel shift right | Shift right + ↓ Emax |
| Emax | Unchanged (surmountable) | Reduced (insurmountable) |
| Overcome by more agonist? | Yes | No |
| Example | Atropine vs ACh; naloxone vs morphine; propranolol | Phenoxybenzamine (α), aspirin on COX, omeprazole on H⁺/K⁺-ATPase |
High-yield: Phenoxybenzamine is the classic irreversible (non-equilibrium) competitive antagonist — used in phaeochromocytoma; its block cannot be overcome by surging catecholamines.
Other antagonism types:
- Physiological/functional — two drugs, opposite effects, different receptors (adrenaline vs histamine in anaphylaxis).
- Chemical — antagonist binds the drug itself (protamine + heparin; chelators + metals).
- Pharmacokinetic — one alters absorption/metabolism/excretion of the other (enzyme induction).
8. Receptor regulation & related concepts
- Down-regulation / desensitisation: Prolonged agonist exposure → ↓ receptor number or responsiveness (tachyphylaxis). GPCR desensitisation involves β-arrestin and GRK-mediated phosphorylation. Example: tolerance to β-agonists.
- Up-regulation / supersensitivity: Chronic antagonism or denervation → ↑ receptors → rebound on withdrawal (β-blocker withdrawal → rebound tachycardia/angina; explains denervation supersensitivity).
- Tachyphylaxis: Rapid tolerance over minutes-hours, e.g. ephedrine, nicotine, amphetamine (depletes vesicular stores).
High-yield: Abrupt clonidine withdrawal → rebound hypertension (α₂ up-regulation + ↑NA release). Abrupt β-blocker withdrawal → rebound angina/MI. Always taper.
9. Clinical / pharmacological correlations (drug ↔ receptor)
| Drug class | Receptor / target | Coupling |
|---|---|---|
| Salbutamol | β₂ adrenergic | Gs → ↑cAMP → bronchodilation |
| Clonidine, α-methyldopa | α₂ adrenergic (central) | Gi → ↓cAMP → ↓sympathetic outflow |
| Prazosin | α₁ adrenergic | blocks Gq → vasodilation |
| Atropine | M (muscarinic) | blocks Gi/Gq |
| Morphine | μ-opioid | Gi → ↓cAMP, ↑K⁺, ↓Ca²⁺ |
| Ondansetron | 5-HT₃ | ion channel block |
| Sildenafil | PDE-5 | ↑cGMP indirectly |
| Insulin | insulin receptor | tyrosine kinase |
| Prednisolone | glucocorticoid receptor | nuclear/transcription |
10. Key differentials & common confusions
- Potency vs efficacy: A low-dose drug is not necessarily superior; efficacy (Emax) matters clinically (e.g. furosemide > thiazide in efficacy regardless of potency).
- Partial agonist vs antagonist: A partial agonist gives a ceiling effect and behaves as a functional antagonist when a full agonist is present (buprenorphine can precipitate withdrawal in opioid-dependent patients).
- Competitive vs non-competitive antagonism (Emax preserved vs reduced).
- GABA-A (Cl⁻ channel) vs GABA-B (GPCR-Gi).
- Soluble guanylyl cyclase (NO/nitrates) vs membrane guanylyl cyclase (ANP).
Recently asked / exam angle
- Match the receptor to its G-protein: β → Gs, α₂/M₂/D₂ → Gi, α₁/M₁/M₃ → Gq (almost guaranteed).
- Which receptor uses IP₃/DAG? → Gq-coupled (α₁, M₁, M₃, H₁, 5-HT₂, AT₁).
- Cholera toxin acts on Gs; pertussis toxin acts on Gi — predict the cAMP change.
- Insulin works through which mechanism? → Receptor tyrosine kinase.
- GH/EPO/prolactin/leptin signalling? → JAK-STAT.
- Fastest vs slowest receptor superfamily (ms → hours).
- Phenoxybenzamine = irreversible antagonist; its dose-response curve shows ↓Emax.
- Effect of spare receptors on EC50 (lowers it / increases sensitivity).
- ANP and its second messenger → cGMP via membrane guanylyl cyclase.
- Barbiturate vs benzodiazepine effect on the GABA-A chloride channel (duration vs frequency).
Rapid revision
- Four families: ion channel (ms) → GPCR (s) → enzyme-linked (min) → nuclear (hr).
- Gs → ↑cAMP; Gi → ↓cAMP; Gq → IP₃/DAG → Ca²⁺ + PKC.
- β, D₁, H₂, glucagon = Gs; α₂, M₂, D₂, opioid, GABA-B = Gi; α₁, M₁/M₃, H₁, 5-HT₂ = Gq.
- Cholera toxin locks Gs ON; pertussis toxin locks Gi OFF → both raise cAMP.
- Methylxanthines inhibit PDE → ↑cAMP; sildenafil inhibits PDE-5 → ↑cGMP.
- GABA-A & glycine = inhibitory Cl⁻ channels; benzodiazepines ↑frequency, barbiturates ↑duration.
- Insulin/EGF/VEGF = receptor tyrosine kinase; GH/prolactin/EPO/leptin/interferon = JAK-STAT.
- ANP → membrane guanylyl cyclase → cGMP; NO/nitrates → soluble GC → cGMP.
- Steroids & T3 = nuclear receptors → slow onset, long action; T3/VitD/retinoid heterodimerise with RXR.
- Competitive antagonist → right shift, Emax unchanged (surmountable); irreversible → Emax reduced.
- Phenoxybenzamine = irreversible α-blocker (phaeochromocytoma); aspirin/omeprazole = irreversible targets.
- Spare receptors lower EC50 (↑sensitivity); chronic agonist → down-regulation; chronic antagonist → up-regulation (clonidine/β-blocker rebound).