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. α(1B) channels are much more strongly modulated than α(1E) channels. To understand the structural basis for this difference, we have constructed and expressed various α(1B) and α(1E) chimeric Ca channels and examined their regulation by κ-opioid receptors. Replacement of the first membrane-spanning domain of α(1E) with the corresponding region of α(1B) resulted in a chimeric Ca channel that was modulated by κ-opioid receptors to a significantly greater extent than α(1E). Transfer of the N terminus and I/II loop from α(1B) in addition to domain I resulted in a chimeric channel that was modulated to the same extent as α(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.