Feedback inhibition of Ca(2+) channels by Ca(2+) depends on a short sequence of the C terminus that does not include the Ca(2+)-binding function of a motif with similarity to Ca(2+)-binding domains

α(1C)- and α(1E)-based Ca(2+) channels differ in that the former are inhibited by Ca(2+) entering through its pore, while the latter are not. It has been proposed on the basis of analysis of α(1E)/α(1C) chimeras that the molecular determinants responsible for Ca(2+) inhibition involve both a conserved Ca(2+)-binding motif (EF hand) plus additional sequences located C-terminal to the EF hand. Through construction of similar α(1E)/α(1C) chimeras, we transferred Ca(2+) inhibition from α(1C) to α(1E) by replacing a 134-aa segment of α(1E) with the homologous 142-aa segment of α(1C). This segment is located immediately after the proposed Ca(2+)-binding EF hand motif. Replacement of the α(1C) EF hand with the corresponding EF hand of α(1E) did not interfere with inhibition of α(1C) by Ca(2+), and a triple mutant of α(1C), α(1C)[D1535A,E1537A,D1546A], that disrupts the potential Ca(2+)-coordinating ability of the EF hand continued to be inhibited by Ca(2+). These results indicate that a small portion of the α(1C) C terminus is essential for inhibition by Ca(2+) and place the Ca(2+)-binding site anywhere in α(1C), with the exception of its EF hand-like motif.