STRUCTURAL FEATURES DETERMINING DIFFERENTIAL RECEPTOR REGULATION OF NEURONAL CA CHANNELS

Dihydropyridine-insensitive Ca channels are subject to direct receptor G-protein-mediated inhibition to differing extents. alpha(1B) channel s are much more strongly modulated than alpha(1E) channels. To underst and the structural basis for this difference, we have constructed and expressed various alpha(1B) and alpha(1E) chimeric Ca channels and exa mined their regulation by kappa-opioid receptors. Replacement of the f irst membrane-spanning domain of alpha(1E) with the corresponding regi on of alpha(1B) resulted in a chimeric Ca channel that was modulated b y kappa-opioid receptors to a significantly greater extent than alpha( 1E). Transfer of the N terminus and I/II loop from alpha(1B) in additi on to domain I resulted in a chimeric channel that was modulated to th e same extent as alpha(1B). Other regions of the molecule do not appea r to contribute significantly to the degree of inhibition obtained, al though the C terminus may contribute to facilitation.