Unique regulatory properties of the type 2a Ca2+ channel β subunit caused by palmitoylation

beta subunits of voltage-gated Ca2+ 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 beta 2a, which differs in that it does not support prepulse facilitation of alpha(1C) Ca2+ channels, inhibits voltage-induced inactivation of neuronal alpha(1E) Ca2+ channels, and is more effective in blocking inhibition of alpha(1E) channels by G protein-coupled receptors. We show that the distinguishing properties of beta 2a, rather than interaction with a distinct site of alpha(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 beta 2a were lost in a mutant that could not be palmitoylated [beta 2a(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 beta 2 splice variants differing only in their N-termini.