Ion Channels and Human Disorders


The human channelopathies are a rapidly expanding group of primarily genetic conditions. They are characterised by dysfunction of membrane‐bound glycoproteins (ion channels). Several neurological and general medical disorders have been shown to be owing to underlying ion‐channel dysfunction and genetic analysis is now often a routine clinical practice. These disorders exhibit extensive phenotypic and genetic heterogeneity with many distinct diseases caused by dysfunction of the same channel by differing mechanisms. With the advent of the next‐generation sequencing, we are discovering even greater genetic heterogeneity and our understanding of the mechanisms behind these diseases continues to extend as more functional analysis is performed and new techniques are developed. In the future, this will lead to the identification of better targeted treatments for these diseases.

Key Concepts

  • Channelopathies are commonly owing to mutations in functionally important regions of either pore‐forming or auxiliary channel subunits resulting in episodic disorders.
  • Mutations often cause disease by altering channel gating, voltage dependence or channel assembly and now there is also evidence for effects in posttranslational modification.
  • Channelopathies are now understood to present either with intermittent symptoms which may completely recover, have a secondary progression or may be a severe primary progressive disease. The location and type of the mutation often influence this.
  • Genetic heterogeneity is very common amongst the channelopathies and is likely to increase with the use of modern genetic analysis.
  • Channelopathies, such as myotonia congenita, have extensive phenotypic variability even within a single pedigree, making it difficult to predict and give accurate genetic counselling.

Keywords: channelopathy; myotonia; migraine; epilepsy; episodic ataxia; spinocerebellar ataxia

Figure 1. Schematic diagram demonstrating the main components of an ion channel. (a) Pore‐forming subunit; (b) aqueous pore; (c) ion selectivity filter; (d) voltage sensor; (e) gating mechanism and (f) auxiliary subunits.
Figure 2. (a) Representation of the membrane topology of the chloride channel. (b) Schematic diagram of the double‐barrelled ClC‐l channel. This shows two separate pores formed by each ClC‐l subunit.
Figure 3. (a) Membrane topology of the α subunit of the voltage‐gated calcium channel. Each domain (DI–IV) consists of six transmembrane segments (S1–6). The fourth segment (S4) in each domain acts as a voltage sensor. (b) Locations of EA2 (green circles), FHM (red circles) and SCA6 (blue) mutations in CACNA1A. (c) Representation of the P/Q‐type calcium channel with the central pore‐forming subunit (α1) and its auxiliary subunits (α2, β, γ and δ).
Figure 4. Tetramerisation of Kv1.1 subunits (α) with associated β subunits forming the voltage‐gated potassium channel.


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Further Reading

Cannon SC (2006) Pathomechanisms in channelopathies of skeletal muscle and brain. Annual Review of Neuroscience 29: 387–415.

Catterall WA, Dib‐Hajj S, Meisler MH and Pietrobon D (2008) Inherited neuronal ion channelopathies: new windows on complex neurological diseases. Journal of Neuroscience 28 (46): 11768–11777.

Matthews E, Fialho D, Tan SV, et al. (2010) The non‐dystrophic myotonias: molecular pathogenesis, diagnosis and treatment. Brain 133 (Pt 1): 9–22.

Pietrobon D (2010) Ca(V)2.1 channelopathies. Pflügers Archiv 460 (2): 375–393.

Spillane J, Kullmann DM and Hanna MG (2016) Genetic neurological channelopathies: molecular genetics and clinical phenotypes. Journal of Neurology, Neurosurgery and Psychiatry 87: 37–48.

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Raja Rayan, Dipa L, and Hanna, Michael G(Jan 2018) Ion Channels and Human Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005166.pub3]