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The Journal of Neuroscience, March 11, 2009, 29(10):3242-3251; doi:10.1523/JNEUROSCI.4767-08.2009

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Cellular/Molecular
The Dipeptidyl-Peptidase-Like Protein DPP6 Determines the Unitary Conductance of Neuronal Kv4.2 Channels

Yuri A. Kaulin,^1 * José A. De Santiago-Castillo,^1 * Carmen A. Rocha,¹ Marcela S. Nadal,² Bernardo Rudy,² and Manuel Covarrubias¹

¹Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and ²Department of Physiology and Neuroscience, Smilow Neuroscience Program, New York University School of Medicine, New York, New York 10016

Correspondence should be addressed to Dr. Yuri A. Kaulin, Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107. Email: yuri.kaulin{at}jefferson.edu

The neuronal subthreshold-operating A-type K⁺ current regulates electrical excitability, spike timing, and synaptic integration and plasticity. The Kv4 channels underlying this current have been implicated in epilepsy, regulation of dopamine release, and pain plasticity. However, the unitary conductance () of neuronal somatodendritic A-type K⁺ channels composed of Kv4 pore-forming subunits is larger (7.5 pS) than that of Kv4 channels expressed singly in heterologous cells (4 pS). Here, we examined the putative novel contribution of the dipeptidyl-peptidase-like protein-6 DPP6-S to the of native [cerebellar granule neuron (CGN)] and reconstituted Kv4.2 channels. Coexpression of Kv4.2 proteins with DPP6-S was sufficient to match the of native CGN channels; and CGN Kv4 channels from dpp6 knock-out mice yielded a indistinguishable from that of Kv4.2 channels expressed singly. Moreover, suggesting electrostatic interactions, charge neutralization mutations of two N-terminal acidic residues in DPP6-S eliminated the increase in . Therefore, DPP6-S, as a membrane protein extrinsic to the pore domain, is necessary and sufficient to explain a fundamental difference between native and recombinant Kv4 channels. These observations may help to understand the molecular basis of neurological disorders correlated with recently identified human mutations in the dpp6 gene.

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Received Oct. 3, 2008; revised Jan. 13, 2009; accepted Feb. 2, 2009.

Correspondence should be addressed to Dr. Yuri A. Kaulin, Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107. Email: yuri.kaulin{at}jefferson.edu

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