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The Journal of Neuroscience, March 21, 2007, 27(12):3317-3327; doi:10.1523/JNEUROSCI.4566-06.2007

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Cellular/Molecular
Inhibition of Recombinant N-Type Ca_V Channels by the ₂ Subunit Involves Unfolded Protein Response (UPR)-Dependent and UPR-Independent Mechanisms

Alejandro Sandoval,^1,3 Arturo Andrade,¹ Aaron M. Beedle,⁴ Kevin P. Campbell,⁴ and Ricardo Felix²

¹Departments of Physiology, Biophysics, and Neuroscience, and ²Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, Mexico City, 07300, Mexico, ³School of Medicine Faculty of Superior Studies Iztacala, National Autonomous University of Mexico, Tlalnepantla, 54090, Mexico, and ⁴Howard Hughes Medical Institute and Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242-1101

Correspondence should be addressed to Dr. Ricardo Felix, Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional #2508, Colonia Zacatenco, México D.F., CP 07300, México. Email: rfelix{at}fisio.cinvestav.mx

Auxiliary subunits are an important component of high-voltage-activated calcium (Ca_V) channels, but their precise regulatory role remains to be determined. In the current report, we have used complementary approaches including molecular biology and electrophysiology to investigate the influence of the subunits on neuronal Ca_V channel activity and expression. We found that coexpression of ₂ or ₃ subunits drastically inhibited macroscopic currents through recombinant N-type channels (Ca_V2.2/ß₃/₂) in HEK-293 cells. Using inhibitors of internalization, we found that removal of functional channels from the plasma membrane is an improbable mechanism of current regulation by . Instead, changes in current amplitude could be attributed to two distinct mechanisms. First, subunit expression altered the voltage dependence of channel activity. Second, subunit expression reduced N-type channel synthesis via activation of the endoplasmic reticulum unfolded protein response. Together, our findings (1) corroborate that neuronal subunits significantly downregulate Ca_V2.2 channel activity, (2) uncover a role for the ₂ subunit in Ca_V2.2 channel expression through early components of the biosynthetic pathway, and (3) suggest that, under certain conditions, channel protein misfolding could be induced by interactions with the subunits, supporting the notion that Ca_V channels constitute a class of difficult-to-fold proteins.

Key words: Ca²⁺ channels; ; subunit; genistein; HEK-293 cells; PERK; UPR

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Received Oct. 20, 2006; revised Feb. 15, 2007; accepted Feb. 16, 2007.

Correspondence should be addressed to Dr. Ricardo Felix, Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional #2508, Colonia Zacatenco, México D.F., CP 07300, México. Email: rfelix{at}fisio.cinvestav.mx

This article has been cited by other articles:

				L. Ferron, A. Davies, K. M. Page, D. J. Cox, J. Leroy, D. Waithe, A. J. Butcher, P. Sellaturay, S. Bolsover, W. S. Pratt, et al. The Stargazin-Related Protein {gamma}7 Interacts with the mRNA-Binding Protein Heterogeneous Nuclear Ribonucleoprotein A2 and Regulates the Stability of Specific mRNAs, Including CaV2.2 J. Neurosci., October 15, 2008; 28(42): 10604 - 10617. [Abstract] [Full Text] [PDF]

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