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The Journal of Neuroscience, September 7, 2005, 25(36):8282-8294; doi:10.1523/JNEUROSCI.2253-05.2005

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Cellular/Molecular
Developmental Activation of Calmodulin-Dependent Facilitation of Cerebellar P-Type Ca²⁺ Current

Dipayan Chaudhuri,¹ Badr A. Alseikhan,² Siao Yun Chang,^3,4 Tuck Wah Soong,^3,4 and David T. Yue^1,2

Departments of ¹Neuroscience and ²Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ³National Neuroscience Institute, Singapore 308433, and ⁴Department of Physiology, National University of Singapore, Singapore 117597

P-type (Ca_V2.1) Ca²⁺ channels are a central conduit of neuronal Ca²⁺ entry, so their Ca²⁺ feedback regulation promises widespread neurobiological impact. Heterologous expression of recombinant Ca_V2.1 channels demonstrates that the Ca²⁺ sensor calmodulin can trigger Ca²⁺-dependent facilitation (CDF) of channel opening. This facilitation occurs when local Ca²⁺ influx through individual channels selectively activates the C-terminal lobe of calmodulin. In neurons, however, such calmodulin-mediated processes have yet to be detected, and CDF of native P-type current has thus far appeared different, arguably triggered by other Ca²⁺ sensing molecules. Here, in cerebellar Purkinje somata abundant with prototypic P-type channels, we find that the C-terminal lobe of calmodulin does produce CDF, and such facilitation augments Ca²⁺ entry during stimulation by repetitive action-potential and complex-spike waveforms. Beyond recapitulating key features of recombinant channels, these neurons exhibit an additional modulatory dimension: developmental upregulation of CDF during postnatal week 2. This phenomenon reflects increasing somatic expression of Ca_V2.1 splice variants that manifest CDF and progressive dendritic targeting of variants lacking CDF. Calmodulin-triggered facilitation is thus fundamental to native Ca_V2.1 and rapidly enhanced during early development.

Key words: P/Q-type channel; 1A; alternative splicing; EF hand; cerebellar Purkinje neuron; short-term synaptic plasticity

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Received June 2, 2005; revised July 31, 2005; accepted July 31, 2005.

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