Abstract
The cardiac voltage-gated Ca(2+) channel, Ca(v)1.2, mediates excitation-contraction coupling in the heart. The molecular composition of the channel includes the pore-forming α1 subunit and auxiliary α2/δ-1 and β subunits. Ca(2+) channel γ subunits, of which there are 8 isoforms, consist of 4 transmembrane domains with intracellular N- and C-terminal ends. The γ1 subunit was initially detected in the skeletal muscle Ca(v)1.1 channel complex, modulating current amplitude and activation and inactivation properties. The γ1 subunit also shifts the steady-state inactivation to more negative membrane potentials, accelerates current inactivation, and increases peak currents, when coexpressed with the cardiac α1c subunit in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. The γ1 subunit is not expressed, however, in cardiac muscle. We sought to determine whether γ subunits that are expressed in cardiac tissue physically associate with and modulate Ca(v)1.2 function. We now demonstrate that γ4, γ6, γ7, and γ8 subunits physically interact with the Ca(v)1.2 complex. The γ subunits differentially modulate Ca(2+) channel function when coexpressed with the β1b and α2/δ-1 subunits in HEK cells, altering both activation and inactivation properties. The effects of γ on Ca(v)1.2 function are dependent on the subtype of β 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.