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The Journal of Neuroscience, May 15, 1998, 18(10):3689-3698

Structural Features Determining Differential Receptor Regulation of Neuronal Ca Channels

Arthur A. Simen and Richard J. Miller

Department of Pharmacological and Physiological Sciences, Committee on Neurobiology, University of Chicago, Chicago, Illinois 60637

Dihydropyridine-insensitive Ca channels are subject to direct receptor G-protein-mediated inhibition to differing extents. alpha 1B channels are much more strongly modulated than alpha 1E channels. To understand the structural basis for this difference, we have constructed and expressed various alpha 1B and alpha 1E chimeric Ca channels and examined their regulation by kappa -opioid receptors. Replacement of the first membrane-spanning domain of alpha 1E with the corresponding region of alpha 1B resulted in a chimeric Ca channel that was modulated by kappa -opioid receptors to a significantly greater extent than alpha 1E. Transfer of the N terminus and I/II loop from alpha 1B in addition to domain I resulted in a chimeric channel that was modulated to the same extent as alpha 1B. Other regions of the molecule do not appear to contribute significantly to the degree of inhibition obtained, although the C terminus may contribute to facilitation.

Key words: calcium channels; G-proteins; opioid receptors; modulation; structure-function; inverse agonism

Copyright © 1998 Society for Neuroscience  0270-6474/98/18103689-10$05.00/0


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