Feedback inhibition of Ca2+ channels by Ca2+ depends on a short sequence of the C terminus that does not include the Ca2+ -binding function of a motif with similarity to Ca2+ -binding domains.

alpha(1C)- and alpha(1E)-based Ca2+ channels differ in that the former are inhibited by Ca2+ entering through its pore, while the latter are not. It has been proposed on the basis of analysis of alpha(1E)/alpha(1C) chimeras that the molecular determinants responsible for Ca2+ inhibition involve both a conserved Ca2+-binding motif (EF hand) plus additional sequences located C-terminal to the EF hand. Through construction of similar alpha(1E)/alpha(1C) chimeras, we transferred Ca2+ inhibition from alpha(1C) to alpha(1E) by replacing a 134-aa segment of alpha(1E) with the homologous 142-aa segment of alpha(1C). This segment is located immediately after the proposed Ca2+ -binding EF hand motif. Replacement of the alpha(1C) EF hand with the corresponding EF hand of alpha(1E) did not interfere with inhibition of alpha(1C) by Ca2+, and a triple mutant of alpha(1C), alpha(1C)[D1535A,E1537A,D1546A], that disrupts the potential Ca2+-coordinating ability of the EF hand continued to be inhibited by Ca2+. These results indicate that a small portion of the alpha(1C) C terminus is essential for inhibition by Ca2+ and place the Ca2+ -binding site anywhere in alpha(1C), with the exception of its EF hand-like motif.