J Med Genet 2000;37:729–740 729 Review article J Med Genet: first published as 10.1136/jmg.37.10.729 on 1 October 2000. Downloaded from Channelopathies: ion channel defects linked to heritable clinical disorders Ricardo Felix Abstract number of inherited ion channel diseases Electrical signals are critical for the func- named collectively “channelopathies”, caused tion of neurones, muscle cells, and cardiac by mutations in K+,Na+,Ca2+, and Cl- channels myocytes. Proteins that regulate electrical that are known to exist in human and animal signalling in these cells, including voltage models. gated ion channels, are logical sites where Ion channels constitute a class of macromo- abnormality might lead to disease. Ge- lecular protein tunnels that span the lipid netic and biophysical approaches are bilayer of the cell membrane, which allow ions being used to show that several disorders to flow in or out of the cell in a very eYcient result from mutations in voltage gated ion fashion (up to 106 per second). This flow of channels. Understanding gained from ions creates electrical currents (in the order of early studies on the pathogenesis of a 10-12 to 10-10 amperes per channel) large enough group of muscle diseases that are similar to produce rapid changes in the transmem- in their episodic nature (periodic paraly- brane voltage, which is the electrical potential sis) showed that these disorders result diVerence between the cell interior and exte- from mutations in a gene encoding a volt- rior. Inasmuch as Na+ and Ca2+ ions are at age gated Na+ channel. Their characteri- higher concentrations extracellularly than in- sation as channelopathies has served as a tracellularly, openings of Na+ and Ca2+ chan- paradigm for other episodic disorders. nels cause these cations to enter the cell and For example, migraine headache and depolarise the membrane. In contrast, when K+ some forms of epilepsy have been shown leavesorCl- enters the cell through open chan- http://jmg.bmj.com/ to result from mutations in voltage gated nels, the cell interior becomes more negative, Ca2+ channel genes, while long QT syn- or hyperpolarised. Ion channels in general can drome is known to result from mutations be either open or closed. The process of transi- in either K+ or Na+ channel genes. This tion from the open to the closed state (and vice article reviews progress made in the com- versa) is known as gating. Some channels open plementary fields of molecular genetics and close randomly at all membrane potentials. and cellular electrophysiology which has Their gating is said to be voltage independent. led to a better understanding of voltage Other ion channels are normally closed but on September 29, 2021 by guest. Protected copyright. gated ion channelopathies in humans and their open probability can be greatly enhanced mice. by a change in membrane potential (voltage (J Med Genet 2000;37:729–740) gated channels), by the binding of extracellular Keywords: ion channel genetics; ion channel physiopa- or intracellular ligands (ligand gated channels), thology; channelopathies; hereditary diseases or by physical stimuli (mechano and heat sen- sitive channels). When an ion channel opens, permeant ions are able to move through it, and Department of Many interesting advances in molecular medi- the direction in which they move, as mentioned Physiology, Biophysics, and cine over the last few years have come from above, is governed by the electrochemical Neuroscience, Center research in molecular genetics. Virtually every gradient that represents the sum of the chemi- for Research and month novel genes linked to diVerent clinical cal gradient across the plasma membrane and Advanced Studies of disorders are cloned. Sometimes these findings the electrical field experienced by the ion. the National relate to common diseases, while other times Nevertheless, the movement of an ion through Polytechnic Institute they concern diseases that are fairly rare. In any an open channel is not only a function of its (Cinvestav-IPN), Mexico case, the information often provides important electrochemical gradient. It is also dependent R Felix insight into mechanisms underlying a particu- on the relative permeability of the channel to lar disease, or new means of understanding the the ion, which is determined by several factors Correspondence to: function of a particular protein. A good exam- including the relative sizes of the ion and the Dr Felix, Departmento de Fisiología Biofísica y ple of this is the field of ion channel research. In pore of the channel. However, ion channels do Neurociencias, parallel with the progress in the understanding not act only as molecular sieves that allow the Cinvestav-IPN, Avenida IPN of the structure and function of these proteins, free diVusion of ions below a certain size. 2508, Colonia Zacatenco, México DF, CP 07000, the list of genetic diseases linked to them has Rather, they can discriminate in the kind of rfelix@fisio.cinvestav.mx grown rapidly. Today there are a considerable ions to which they are permeable. For example, www.jmedgenet.com 730 Felix + + Na channels are highly permeable to Na but A J Med Genet: first published as 10.1136/jmg.37.10.729 on 1 October 2000. Downloaded from not to K+ ions, whereas K+ channels are ∼100 times more permeable to K+ than to Na+. Because Na+ has a smaller ionic radius than K+, the high selectivity of the channels cannot be simply explained by physical occlusion. This ionic discrimination takes place where the pore Closed of the channel is narrowest, at a region known as the selectivity filter, and it is the amino acids located at the selectivity filter that determine which ions can permeate. Cation selective channels, for example, often have negatively charged residues at, or near, their selectivity fil- ters, which attract positive ions and repel nega- tive ions.12 This review focuses on the voltage gated ion Open Inactivated channels for cations (Na+,K+, and Ca2+), and briefly discusses several recent studies linking a growing number of genetic disorders to genes of the ion channel superfamily, with special B emphasis on those characterised by neurologi- Stimulating cal, neuromuscular, or cardiac dysfunction in current humans and mice. However, in order to be able to put the information on channelopathies in 2 perspective, it is necessary to consider first 50 some molecular aspects of voltage gated ion channel structure and function. Voltage gated ion channels and cellular 3 excitability Voltage gated ion channels can assume either of three major conformational states, closed, Vm (mV) open, or inactivated, and usually respond to 1 membrane depolarisation with a transition from the closed to an open state followed by an –90 intrinsic inactivation (fig 1A).12 Na+ and K+ channel activation and inactivation are the 4 basis of the action potential, the principal inte- grating signal that allows excitable cells to con- 0 100 200 300 400 500 http://jmg.bmj.com/ duct information for the control of a wide Time (ms) range of physiological events including, among Figure 1 Ion channels and electrical excitability. (A) others, propagation of the nerve impulse and Plasma membrane voltage gated channels can adopt at cardiac pacemaking (fig 1B). Furthermore, least three conformational states. At rest, the closed (but not 2+ inactivated) state has the lowest free energy and is therefore Ca channels not only contribute to mem- most stable; however if the membrane is depolarised, the brane polarisation per se, but also play an addi- energy of the open state is lower and the channel opens tional critical role in controlling the influx of allowing ions to flow. The cell is saved from a permanent spasm because the free energy of the inactive state is lower on September 29, 2021 by guest. Protected copyright. this important intracellular regulator. Once still, and after a randomly variable period spent in the open within the cell, Ca2+ interacts with modifying state the channel becomes inactivated (stops conducting). In enzymes, cofactors, and other second messen- this state the channel cannot open again until the membrane potential returns to its initial negative value. gers to influence cellular events ranging from (B) Voltage gated ion channels are responsible for muscle contraction, exocytosis, and enzyme generating transient self-propagating electrical signals called activation to gene expression.23 Voltage gated action potentials. The time course of a prolonged cardiac action potential is illustrated. In this particular case, an ion channels may also participate in the regula- excitatory stimulus that causes a momentary partial tion of many specific functions in non-excitable depolarisation beyond a threshold voltage promptly causes cells. For example, in mammalian sperm voltage gated Na+ channels to open (1) causing further depolarisation of the cell membrane. Na+ channels are then capacitation, a poorly understood maturational + + rapidly inactivated allowing a transient K current to process, a modification of K channel activity, return the action potential to a plateau voltage (2). This occurs that render sperm responsive to stimuli plateau is maintained by the balance between outward and inward moving currents through K+ and Ca2+ channels, leading to the acrosome reaction before 2+ 4 respectively. Progressive inactivation of Ca channels and fertilisation. increasing activation of K+ channels repolarise the cell (3) to the resting membrane potential (4), which is maintained Molecular structure of voltage gated ion by inwardly rectifying K+ channels. channels As mentioned above, ion channels have distinct N- and C-terminal domains of the protein ion selectivity and gating properties, deter- positioned intracellularly. One transmembrane mined at the molecular level by the type of the segment (S4) contains a unique array of pore forming (á) subunit that the channel con- positive charges that function as the voltage tains (fig 2A). The structure of the á subunits is sensor of the channel.