Functional Modularity of the β-Subunit of Voltage-Gated Ca2+ Channels

The β-subunit of voltage-gated Ca2+ channels plays a dual role in chaperoning the channels to the plasma membrane and modulating their gating. It contains five distinct modular domains/regions, including the variable N- and C-terminus, a conserved Src homology 3 (SH3) domain, a conserved guanylate kinase (GK) domain, and a connecting variable and flexible HOOK region. Recent crystallographic studies revealed a highly conserved interaction between the GK domain and α interaction domain (AID), the high-affinity binding site in the pore-forming α1 subunit. Here we show that the AID-GK domain interaction is necessary for β-subunit-stimulated Ca2+ channel surface expression and that the GK domain alone can carry out this function. We also examined the role of each region of all four β-subunit subfamilies in modulating P/Q-type Ca2+ channel gating and demonstrate that the β-subunit functions modularly. Our results support a model that the conserved AID-GK domain interaction anchors the β-subunit to the α1 subunit, enabling α1-β pair-specific low-affinity interactions involving the N-terminus and the HOOK region, which confer on each of the four β-subunit subfamilies its distinctive modulatory properties.