4.2 Ion Channel Receptors
Ion channels are pore-forming membrane proteins that allow rapid ion flux across membranes, generating electrical signals. They represent ~15% of drug targets and are crucial for neuronal, cardiac, and muscle function.
Classification by Gating Mechanism
Ligand-Gated Ion Channels (Ionotropic Receptors)
Open in response to neurotransmitter binding. Fast synaptic transmission (milliseconds).
- • Cys-loop family: Nicotinic ACh (nAChR), GABA_A, glycine, 5-HT3
- • Glutamate receptors: NMDA, AMPA, kainate
- • ATP receptors: P2X purinergic receptors
Voltage-Gated Ion Channels
Open/close in response to membrane potential changes. Critical for action potentials.
- • Na⁺ channels: Neuronal excitability (NaV1.1-1.9)
- • K⁺ channels: Repolarization (Kv, KCa, KATP, Kir)
- • Ca²⁺ channels: L, N, P/Q, R, T-types
- • Cl⁻ channels: ClC family, CFTR
Other Gating Mechanisms
- • Mechanosensitive: TRP channels, Piezo1/2
- • Temperature-sensitive: TRPV1 (heat/capsaicin), TRPM8 (cold/menthol)
- • Second messenger-gated: Cyclic nucleotide-gated (CNG), HCN channels
Ligand-Gated Channels: Key Examples
Nicotinic ACh Receptor (nAChR)
Structure: Pentamer (α2βγδ muscle; various α/β neuronal)
Ion: Na⁺/K⁺ (depolarization)
Agonists: Acetylcholine, nicotine, succinylcholine
Antagonists: Tubocurarine, atracurium (NMJ blockers)
GABA_A Receptor
Structure: Pentamer (typically 2α, 2β, 1γ)
Ion: Cl⁻ (hyperpolarization/inhibition)
Modulators: Benzodiazepines, barbiturates, ethanol (positive)
Antagonists: Bicuculline, flumazenil (BZD antagonist)
NMDA Receptor
Structure: Tetramer (GluN1/GluN2 subunits)
Ion: Na⁺, K⁺, Ca²⁺ (voltage-dependent Mg²⁺ block)
Agonists: Glutamate + glycine (co-agonist required)
Antagonists: Ketamine, memantine, PCP
Glycine Receptor
Structure: Pentamer (α/β subunits)
Ion: Cl⁻ (inhibition in spinal cord/brainstem)
Antagonist: Strychnine (convulsant, no therapeutic use)
Voltage-Gated Channels: Drug Targets
Voltage-Gated Na⁺ Channels
Blockers: Local anesthetics (lidocaine, procaine), antiarrhythmics (Class I: quinidine, procainamide), anticonvulsants (phenytoin, carbamazepine, lamotrigine) | Mechanism: Preferentially bind inactivated state → use-dependent block
Voltage-Gated Ca²⁺ Channels
L-type blockers: Dihydropyridines (amlodipine, nifedipine - vasodilation), phenylalkylamines (verapamil - cardiac), benzothiazepines (diltiazem) | N/P/Q blockers: Ziconotide (intrathecal, severe pain) | T-type: Ethosuximide (absence seizures)
Voltage-Gated K⁺ Channels
Blockers: 4-aminopyridine (increase ACh release), Class III antiarrhythmics (amiodarone, sotalol - prolong action potential) | Openers: Minoxidil (vasodilation), diazoxide (hyperglycemia treatment)
Mechanisms of Drug Action
Pore Blockers
Drug physically occludes ion conduction pathway. Examples: Local anesthetics (Na⁺), Mg²⁺ (NMDA), quaternary ammonium compounds
Gating Modifiers
Alter voltage-dependence or kinetics of opening/closing. Examples: Benzodiazepines (↑ GABA_A open frequency), scorpion toxins (delay Na⁺ inactivation)
Allosteric Modulators
Bind at sites distinct from pore/gate. Positive: BDZs, barbiturates (GABA_A); Negative: Picrotoxin (GABA_A blocker)
Use/State-Dependent Block
Higher affinity for open or inactivated states. Provides selectivity for rapidly firing neurons (seizures, arrhythmias)
Clinical Applications
Therapeutic Areas
- • Anesthesia: Local (Na⁺ block), general (GABA_A modulation)
- • Epilepsy: Na⁺ blockers, Ca²⁺ blockers, GABA_A enhancers
- • Cardiac arrhythmias: Na⁺, K⁺, Ca²⁺ channel blockers
- • Hypertension: Ca²⁺ channel blockers
- • Neuropathic pain: Na⁺ blockers, Ca²⁺ α2δ ligands (gabapentin)
- • Muscle relaxation: nAChR blockers (surgery)
- • Anxiety/sleep: GABA_A modulators (benzodiazepines)
Channelopathies
Genetic ion channel mutations cause diseases: Cystic fibrosis (CFTR Cl⁻), long QT syndrome (cardiac K⁺/Na⁺), epilepsies (various), periodic paralysis (muscle Na⁺/Ca²⁺), migraine (Ca²⁺)