Unique regulatory properties of the type 2a Ca(2+) channel β subunit caused by palmitoylation

β subunits of voltage-gated Ca(2+) channels are encoded in four genes and display additional molecular diversity because of alternative splicing. At the functional level, all forms are very similar except for β2a, which differs in that it does not support prepulse facilitation of α(1C) Ca(2+) channels, inhibits voltage-induced inactivation of neuronal α(1E) Ca(2+) channels, and is more effective in blocking inhibition of α(1E) channels by G protein-coupled receptors. We show that the distinguishing properties of β2a, rather than interaction with a distinct site of α(1), are because of the recently described palmitoylation of cysteines in positions three and four, which also occurs in the Xenopus oocyte. Essentially, all of the distinguishing features of β2a were lost in a mutant that could not be palmitoylated [β2a(Cys(3,4)Ser)]. Because protein palmitoylation is a dynamic process, these findings point to the possibility that regulation of palmitoylation may contribute to activity-dependent neuronal and synaptic plasticity. Evidence is presented that there may exist as many as three β2 splice variants differing only in their N-termini.