A new beta subtype-specific interaction in alpha(1A) subunit controls P/Q-type Ca2+ channel activation

The cytoplasmic beta subunit of voltage-dependent calcium channels modulate s channel properties in a subtype-specific manner and is important in chann el targeting. A high affinity interaction site between the alpha(1) interac tion domain (AID) in the I-II cytoplasmic loop of alpha(1) and the beta int eraction domain (BID) of the beta subunit is highly conserved among subunit subtypes. We describe a new subtype-specific interaction (Ss1) between the amino-terminal cytoplasmic domain of alpha(1A) (BI-2) and the carboxyl ter minus of beta(4). Like the interaction identified previously (21) between t he carboxyl termini of alpha(1A) and beta(4) (Ss2), the affinity of this in teraction is lower than AID-BID, suggesting that these are secondary intera ctions. Ss1 and Ss2 involve overlapping sites on beta(4) and are competitiv e, but neither inhibits the interaction with AID. The interaction with the amino terminus of alpha(1) is isoform-dependent, suggesting a role in the s pecificity of alpha(1)-beta pairing. Coexpression of beta(4) in Xenopus ooc ytes produces a reduced hyperpolarizing shift in the I-V curve of the (alph a(1A) channel compared with beta(3) (not exhibiting this interaction). Repl acing the amino terminus of alpha(1A) with that of alpha(1c) abolishes this difference. Our data contribute to our understanding of the molecular orga nization of calcium channels, providing a functional basis for variation in subunit composition of native P/Q-type channels.