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The Journal of Neuroscience, October 15, 2000, 20(20):7564-7570

C-Terminal Alternative Splicing Changes the Gating Properties of a Human Spinal Cord Calcium Channel 1A Subunit

Howard S. Krovetz, Thomas D. Helton, Anne L. Crews, and William A. Horne

Department of Anatomy, Physiological Sciences, and Radiology, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina 27606

The calcium channel _1A subunit gene codes for proteins with diverse structure and function. This diversity may be important for fine tuning neurotransmitter release at central and peripheral synapses. The _1A C terminus, which serves a critical role in processing information from intracellular signaling molecules, is capable of undergoing extensive alternative splicing. The purpose of this study was to determine the extent to which C-terminal alternative splicing affects some of the fundamental biophysical properties of _1A subunits. Specifically, the biophysical properties of two alternatively spliced _1A subunits were compared. One variant was identical to an isoform identified previously in human brain, and the other was a novel isoform isolated from human spinal cord. The variants differed by two amino acids (NP) in the extracellular linker between transmembrane segments IVS3 and IVS4 and in two C-terminal regions encoded by exons 37 and 44. Expression in Xenopus oocytes demonstrated that the two variants were similar with respect to current-voltage relationships and the voltage dependence of steady-state activation and inactivation. However, the rates of activation, inactivation, deactivation, and recovery from inactivation were all significantly slower for the spinal cord variant. A chimeric strategy demonstrated that the inclusion of the sequence encoded by exon 44 specifically affects the rate of inactivation. These findings demonstrate that C-terminal structural changes alone can influence the way in which _1A subunits respond to a depolarizing stimulus and add to the developing picture of the C terminus as a critical domain in the regulation of Ca²⁺ channel function.

Key words: spinal cord; cerebellum; calcium channel; 1A subunit; voltage clamp; alternative splicing; C terminus

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20207564-07$05.00/0

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