Childhood Sweetheart vs Late Suitor: CaV Channel Regulation by Auxiliary Beta and Alpha2Delta Subunits

Abstract

High-voltage-activated calcium (CaV) channels link electrical signals to the inflow of Ca2+ ions that trigger biological responses in excitable cells. CaV channels are macromolecular complexes containing pore-forming alpha1 proteins minimally assembled with auxiliary beta and alpha2delta subunits. Both CaVbeta and alpha2delta subunits augment CaV channel currents by enhancing alpha1 trafficking to the cell surface. Whereas CaVbeta (the childhood sweetheart) associates early with alpha1 in the endoplasmic reticulum and promotes forward trafficking, alpha2delta (the late suitor) enhances CaV surface density by stabilizing mature channels at the plasma membrane. Beyond their direct regulatory effects on CaV channels, CaVbeta and alpha2delta are the physical targets for powerful channel modulation by small monomeric G-proteins (RGK) and the anti-epileptic drug, gabapentin, respectively. I will discuss our findings on the different determinants and mechanisms underlying CaV channel regulation by CaVbeta and alpha2delta subunits, and implications of the work for physiological and therapeutic modulation of CaV channels.