The Physiology and Pharmacology of Ion Channels

By Dillon Lim - Medicine Student @ Brasenose College, Oxford

Ion channels are proteins which sit in the plasma membrane to let ions (which are normally impermeant through the lipid bilayer) pass through. These are present most importantly in excitable tissues like nerve and muscle. The movement of ions (as charged particles) is also a flow of current, and can therefore depolarise or repolarise cells; sometimes the ions themselves act as a signal (one important example is Ca2+). These are not pumps or transporters: ions move passively, down an electrochemical (combination of charge and chemical) gradient.


Some of these channels are open all the time (therefore sometimes called leak channels). Others open and close in response to stimuli. The two most common types (certainly in humans) are the ligand- and the voltage-gated channels. When a ligand binds to a ligand-gated channel there is a conformational change in the protein that moves hydrophobic amino acids away from and hydrophilic amino acids towards a central pore through which ions can pass. As you might expect, hydrophobic amino acids block the passage of charged particles such as ions through the pore, while hydrophilic amino acids facilitate movement. Voltage-gated channels operate on the same hydrophobic/hydrophilic principle, but they typically open instead in response to a cell depolarising, that is, the inside becoming more positive. The way this is done is ingenious – positively charged amino acids are placed at regular intervals on a protein (α-)helix. When the cell depolarises, the positively charged side chains are repelled out of the cell, the helix rotates, and it’s this conformational change that causes the pore to open.


In electrically excitable tissues, action potentials are triggered by a small depolarisation induced by the opening of a ligand-gated channel – usually a non-specific influx of cations. This then opens (usually more specific) voltage-gated channels in the membrane, such as the voltage-gated sodium channel (VGSC), causing a larger depolarising flow to evoke an action potential. In skeletal muscle, action potentials cause the muscle to contract; in neurons, action potentials are necessary for the conduction of information down an axon.


What are the practical applications of this? Local anaesthetics, such as lidocaine, block VGSCs. Na+ channels are present on all types of neuron, but pain-sensitive fibres are preferentially blocked because they are the smallest and have the fewest number of channels. This prevents pain signals from being transmitted, and therefore induces anaesthesia. Local anaesthetics also can be used to block “early” heartbeats in cardiac muscle in treatment of some dysrhythmias.


Muscle relaxants affect (nicotinic) acetylcholine receptors, a ligand-gated ion channel normally involved in causing muscle contraction. The “non-depolarising” blockers (like vecuronium) competitively inhibit acetylcholine from binding; the “depolarising” blockers (like suxamethonium) activate the ligand-gated channel (causing an initial contraction) and eventually cause a desensitisation (resulting in prolonged relaxation). Ca2+ channel blockers are also a fairly common class of drugs for some cardiovascular conditions. Mutated ion channels can result in pathology: one famous example is the voltage-gated potassium channel coded for by the hERG gene, which causes the condition called long QT syndrome.


Further reading:

  1. The BioNinja website has Sixth Form level material on action potentials and local anaesthetics. See https://ib.bioninja.com.au/standard-level/topic-6-human-physiology/65-neurons-and-synapses/action-potential.html and https://ib.bioninja.com.au/options/option-a-neurobiology-and/a5-neuropharmacology/anesthetics.html

  2. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications. https://pubs.acs.org/doi/10.1021/jm501981g

  3. Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function. https://journals.physiology.org/doi/full/10.1152/physrev.00015.2008?rfr_dat=cr_pub%3Dpubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org

  4. Clinical Pharmacology of Local Anaesthetics. https://www.nysora.com/foundations-of-regional-anesthesia/pharmacology/clinical-pharmacology-local-anesthetics/

  5. Drug cabinet: Calcium channel blockers. https://www.bhf.org.uk/informationsupport/heart-matters-magazine/medical/drug-cabinet/calcium-channel-blockers