Ca2+ channel inactivation is a key element in controlling the level of Ca2 entry through voltage-gated Ca2+ channels. Interaction between the pore-fo
rming alpha (1) subunit and the auxiliary beta subunit is known to be a str
ong modulator of voltage-dependent inactivation. Here, we demonstrate that
an N-terminal membrane anchoring site (MAS) of the beta (2a) subunit strong
ly reduces alpha (1A) (Ca(V)2.1) Ca2+ channel inactivation. This effect can
be mimicked by the addition of a transmembrane segment to the N terminus o
f the beta (2a) subunit. Inhibition of inactivation by beta (2a) also requi
res a link between MAS and another important molecular determinant, the bet
a interaction domain (BID). Our data suggest that mobility of the Ca2+ chan
nel I-II loop is necessary for channel inactivation. Interaction of this lo
op with other identified intracellular channel domains may constitute the b
asis of voltage-dependent inactivation. We thus propose a conceptually nove
l mechanism for slowing of inactivation by the beta (2a) subunit, in which
the immobilization of the channel inactivation gate occurs by means of MAS
and BID.