Cardiac L-type calcium channel (Cav1.2) associates with γ subunits

The cardiac voltage-gated Ca2+ channel, Ca(v)1.2, mediates excitation-contraction coupling in the heart. The molecular composition of the channel includes the pore-forming alpha 1 subunit and auxiliary alpha 2/delta-1 and beta subunits. Ca2+ channel gamma subunits, of which there are 8 isoforms, consist of 4 transmembrane domains with intracellular N- and C-terminal ends. The gamma 1 subunit was initially detected in the skeletal muscle Ca(v)1.1 channel complex, modulating current amplitude and activation and inactivation properties. The gamma 1 subunit also shifts the steady-state inactivation to more negative membrane potentials, accelerates current inactivation, and increases peak currents, when coexpressed with the cardiac alpha 1c subunit in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. The gamma 1 subunit is not expressed, however, in cardiac muscle. We sought to determine whether gamma subunits that are expressed in cardiac tissue physically associate with and modulate Ca(v)1.2 function. We now demonstrate that gamma 4, gamma 6, gamma 7, and gamma 8 subunits physically interact with the Ca(v)1.2 complex. The gamma subunits differentially modulate Ca2+ channel function when coexpressed with the beta 1b and alpha 2/delta-1 subunits in HEK cells, altering both activation and inactivation properties. The effects of gamma on Ca(v)1.2 function are dependent on the subtype of beta subunit. Our results identify new members of the cardiac Ca(v)1.2 macromolecular complex and identify a mechanism by which to increase the functional diversity of Ca(v)1.2 channels.-Yang, L., Katchman, A., Morrow, J. P., Doshi, D., Marx, S. A. Cardiac L-type calcium channel (Ca(V)1.2) associates with gamma subunits. FASEB J. 25, 928-936 (2011). www.fasebj.org