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The Journal of Neuroscience, February 18, 2004, 24(7):1707-1718; doi:10.1523/JNEUROSCI.4846-03.2004

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Cellular/Molecular
The CACNA1F Gene Encodes an L-Type Calcium Channel with Unique Biophysical Properties and Tissue Distribution

John E. McRory,¹ Jawed Hamid,² Clinton J. Doering,^2,3 Esperanza Garcia,¹ Robin Parker,⁴ Kevin Hamming,¹ Lina Chen,² Michael Hildebrand,¹ Aaron M. Beedle,² Laura Feldcamp,² Gerald W. Zamponi,² and Terrance P. Snutch¹

¹Biotechnology Laboratory, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3, ²Department of Physiology and Biophysics, Cellular and Molecular Neurobiology Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1, ³NeuroMed Technologies Inc., Vancouver, British Columbia, Canada V6T 1Z4, and ⁴Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada V5Z 1M9

Glutamate release from rod photoreceptors is dependent on a sustained calcium influx through L-type calcium channels. Missense mutations in the CACNA1F gene in patients with incomplete X-linked congenital stationary night blindness implicate the Ca_v1.4 calcium channel subtype. Here, we describe the functional and pharmacological properties of transiently expressed human Ca_v1.4 calcium channels. Ca_v1.4 is shown to encode a dihydropyridine-sensitive calcium channel with unusually slow inactivation kinetics that are not affected by either calcium ions or by coexpression of ancillary calcium channel subunits. Additionally, the channel supports a large window current and activates near -40 mV in 2 mM external calcium, making Ca_v1.4 ideally suited for tonic calcium influx at typical photoreceptor resting potentials. Introduction of base pair changes associated with four incomplete X-linked congenital night blindness mutations showed that only the G369D alteration affected channel activation properties. Immunohistochemical analyses show that, in contrast with previous reports, Ca_v1.4 is widely distributed outside the retina, including in the immune system, thus suggesting a broader role in human physiology.

Key words: calcium channel; retina; night blindness; channelopathies; mast cells; plasma cells

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Received Oct 28, 2003; revised December 1, 2003; accepted December 2, 2003.

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