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Blessed are the pacemakers

Nature Neuroscience volume 9, pages 297–298 (2006)Cite this article

Many neurons, particularly inhibitory neurons in motor areas, express ion channels that cause them to fire rapidly and regularly without input. A paper now presents evidence that an inherited ataxia due to mutation in a P/Q-type calcium channel gene results from compromised pacemaking in cerebellar Purkinje neurons, suggesting a possible therapy.

Episodic ataxia type-2 (EA2) is a rare form of inherited ataxia characterized by attacks of incoordination, vertigo and debilitating migraines. This disease, as well as the related conditions familial hemiplegic migraine type-1 (FHM1) and spinocerebellar ataxia type-6 (SCA6) are all caused by mutations in the same ion channel gene, CACNA1A, which encodes the pore-forming subunit of the P/Q-type voltage-gated calcium channel1,2. These channels are widely expressed throughout the nervous system and are especially abundant in cerebellar Purkinje neurons. (The 'P' in P/Q channels is for Purkinje.) In many neurons, P/Q channels are located on presynaptic terminals where they have a key physiological role: they allow the calcium influx required to trigger neurotransmitter release. Indeed, the autoimmune disease Lambert-Eaton syndrome results from antibodies inappropriately targeted to P/Q channels on motor nerve terminals, leading to reduced synaptic transmission at the neuromuscular synapse. This presynaptic function of P/Q channels, along with their high expression in the cerebellum and the known role of the cerebellum in motor coordination, together indicate that episodic symptoms in EA2 and SCA6 might result from dysfunction of synaptic transmission in cerebellar circuits2. However, P/Q channel mutations can lead to irregular firing of Purkinje neurons in vivo, a deficit difficult to attribute to faulty synaptic inputs3. In this issue, Walter et al. provide a fascinating explanation for how P/Q channel defects lead to this irregular firing, and ultimately how they might cause ataxia4.

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Figure 1: Pacemaking in Purkinje neurons.

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Authors and Affiliations

  1. Department of Neurobiology,

    Thomas S Otis & Joanna C Jen

  2. Department of Neurology, Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, California, USA

    Thomas S Otis & Joanna C Jen

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  1. Thomas S Otis
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  2. Joanna C Jen
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Otis, T., Jen, J. Blessed are the pacemakers. Nat Neurosci 9, 297–298 (2006). https://doi.org/10.1038/nn0306-297

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