Ligand-gated ion channels

Ligand-gated ion channels

Ligand-gated ion channels (LGICs) mediate passive ion flux driven by the electrochemical gradient for the permeant ions. LGICs are gated by the binding of a specific ligand to an orthosteric site(s) that triggers a conformational change that results in the conducting state, or by binding of endogenous, or exogenous, modulators to allosteric sites. LGICs are responsible for fast synaptic transmission in the nervous system and at the somatic neuromuscular junction.

This group contains the excitatory, cation-selective, nicotinic acetylcholine (nAch), 5-HT3, ionotropic glutamate (NMDA, AMPA and kainate receptors) and P2X receptors and the inhibitory, anion-selective, GABAA and glycine receptors as well as acid-sensing (proton-gated) ion channels (ASICs), epithelial sodium channels (ENaC), IP3 receptor and the zinc-activated channel (ZAC). LGICs are generally heteromultimers, with subunits encoded by multiple genes. Multimeric combinatorial diversity leads to the wide variety of receptors reported, with differing pharmacological and biophysical properties and varying patterns of expression within the nervous system and other tissues. The pharmaceutical industry is striving to use this heterogeneity to develop new therapeutic agents with improved discrimination between receptor isoforms and reduced off-target effects.

The epithelial sodium channels (ENaC) mediate sodium reabsorption principally in the aldosterone-sensitive distal part of the nephron and the collecting duct of the kidney, and also in the lung epithelia. In the kidney, these channels are involved blood pressure regulation and are associated with many cardiovascular diseases. The ‘potassium-sparing’ diuretics amiloride and triamterene are ENaC channel blockers.

Acid-sensing (proton-gated) ion channels (ASICs) are involved in fear conditioning, memory formation, and pain sensation

Aberrant LGIC function is associated with many diseases. For example, overactivation of NMDA glutamate receptors may play a part in causing neurotoxic damage in the development of neurodegenerative disorders.

Many prescription drugs exert their effects by modulating the activity of LGICs. Some of the more common drug groups are described below:

Volatile anesthetic drugs used for general anesthesia primarily block the activity of GABA-, glutamate- and glycine-gated LGICs, but different agents have different effects on each receptor, and may block other LGICs. For example, sevoflurane is thought to act as a positive allosteric modulator of the GABAA receptor, but also acts as an NMDA receptor antagonist, potentiates glycine receptor currents, as well as nACh and 5-HT3 receptor currents. Desflurane also acts as a positive allosteric modulator of the GABAA and glycine receptors and as a negative allosteric modulator of nACh receptors. Sevoflurane and desflurane have largely replaced isoflurane except in economically undeveloped areas, where their high cost precludes use. Nitrous oxide, used in surgery and dentistry for its anaesthetic and analgesic effects, directly modulates a broad range of ligand-gated ion channels, and this likely plays a major role in many of its effects. It moderately blocks NMDA and β2-subunit-containing nACh channels, weakly inhibits AMPA, kainate, GABAC, and 5-HT3 receptors, and slightly potentiates GABAA and glycine receptors (see Emmanouil and Quock (2007): Advances in understanding the actions of nitrous oxide).

Gamma-aminobutyric acid analogs (the 'gabapentinoids') such as gabapentin and its conjugated prodrug gabapentin enacarbil (both used to treat epilepsy, neuralgic/neuropathic pain) and pregabalin (used to treat generalised anxiety disorder (GAD), neuropathic pain, post herpetic neuralgia) were thought to act as GABAA receptor agonists and cause inhibitory action like GABA. However, more recent analysis reveals high-affinity gabapentin binding sites on neuronal membranes, subsequently demonstrated to represent the α2δ protein, an accessory component of L-type calcium channels, encoded by gene CACNA2D1 or CACNA2D2- see Rogawski and Bazil (2007): New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels. But whatever the mechanism, the effect of GABA analogs is to inhibit release of monoamine neurotransmitters including norepinephrine, substance P, and glutamate.

Acamprosate (used alongside behavioural therapy to manage alcohol abstinence in alcohol-dependent patients) is another GABA-like drug which appears to stimulate GABAergic inhibitory neurotransmission and antagonise the effects of excitatory amino-acids, particularly glutamate (via antagonism of NMDA receptors).

NMDA receptor antagonists (or channel blockers) such as ketamine (an anesthetic), dextromethorphan (a widely used OTC cough suppressant), phencyclidine (PCP, withdrawn from use as an anesthetic pharmaceutical), and nitrous oxide act principally via inhibition of glutamate NMDA receptors. Dextromethorphan is metabolised to the NMDA antagonist dextrorphan by CYP2D6. Many drugs of this class are used recreationally because of their psychoactive and dissociative effects. 

nAch receptor modulators such as nicotine itself (as nicotine replacement therapy) and the nAch receptor antagonist varenicline are used to aid smoking cessation.