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  • Review Article
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Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS

Nature Reviews Neurology volume 8, pages 86–96 (2012)Cite this article

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Abstract

The past two decades have witnessed the emergence of a new and expanding field of neurological diseases—the genetic ion channelopathies. These disorders arise from mutations in genes that encode ion channel subunits, and manifest as paroxysmal attacks involving the brain or spinal cord, and/or muscle. The voltage-gated P/Q-type calcium channel (P/Q channel) is highly expressed in the cerebellum, hippocampus and cortex of the mammalian brain. The P/Q channel has a fundamental role in mediating fast synaptic transmission at central and peripheral nerve terminals. Autosomal dominant mutations in the CACNA1A gene, which encodes voltage-gated P/Q-type calcium channel subunit α1 (the principal pore-forming subunit of the P/Q channel) are associated with episodic and progressive forms of cerebellar ataxia, familial hemiplegic migraine, vertigo and epilepsy. This Review considers, from both a clinical and genetic perspective, the various neurological phenotypes arising from inherited P/Q channel dysfunction, with a focus on recent advances in the understanding of the pathogenetic mechanisms underlying these disorders.

Key Points

  • The neuronal voltage-gated P/Q-type calcium channel (P/Q channel) has a fundamental role in synaptic transmission in the human CNS

  • Mutations in CACNA1A, which encodes the α1 subunit of the P/Q channel, are associated with episodic ataxia type 2, familial hemiplegic migraine-1 and spinocerebellar ataxia type 6

  • Loss-of-function mutations in CACNA1A are associated with episodic ataxia type 2; clinical features include intermittent ataxia, headache and vertigo, and acetazolamide (a carbonic anhydrase inhibitor) is an effective treatment

  • Gain-of-function missense mutations in CACNA1A are associated with familial hemiplegic migraine-1

  • Spinocerebellar ataxia type 6 is associated with abnormal expansion of a polyglutamine repeat in the C-terminus of the P/Q channel α1 subunit

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Figure 1: The voltage-gated P/Q-type calcium channel (P/Q channel).

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Acknowledgements

The authors' research work is supported by the Wellcome Trust (S. Rajakulendran), the Medical Research Council and Action Medical Research (M. G. Hanna). Part of this work was undertaken at University College Hospital, University College London, UK, which receives a proportion of its funding from the National Institute for Health Research Biomedical Research Center. M. G. Hanna is supported by Medical Research Council grant number G0601943.

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  1. Medical Research Council Center for Neuromuscular Diseases, Box 102, National Hospital for Neurology and Neurosurgery, Queen Square, WC1N 3BG, London, UK

    Sanjeev Rajakulendran & Michael G. Hanna

  2. Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Place Road, London, W6 8RF, UK

    Diego Kaski

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All three authors wrote the manuscript. S. Rajakulendran and D. Kaski researched data for the article, S. Rajakulendran contributed to discussions of the content, and S. Rajakulendran and M. G. Hanna undertook review and/or editing of the manuscript before submission.

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Rajakulendran, S., Kaski, D. & Hanna, M. Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS. Nat Rev Neurol 8, 86–96 (2012). https://doi.org/10.1038/nrneurol.2011.228

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