Protein kinase C enhances plasma membrane expression of cardiac L-type calcium channel,CaV1.2

L-type-voltage-dependent Ca²⁺ channels (L-VDCCs; Ca_V1.2, α_1C), crucial in cardiovascular physiology and pathology, are modulated via activation of G-protein-coupled receptors and subsequently protein kinase C (PKC). Despite extensive study, key aspects of the mechanisms leading to PKC-induced Ca²⁺ current increase are unresolved. A notable residue, Ser1928, located in the distal C-terminus (dCT) of α_1C was shown to be phosphorylated by PKC. Ca_V1.2 undergoes posttranslational modifications yielding full-length and proteolytically cleaved CT-truncated forms. We have previously shown that, in Xenopus oocytes, activation of PKC enhances α_1C macroscopic currents. This increase depended on the isoform of α_1C expressed. Only isoforms containing the cardiac, long N-terminus (L-NT), were upregulated by PKC. Ser1928 was also crucial for the full effect of PKC. Here we report that, in Xenopus oocytes, following PKC activation the amount of α_1C protein expressed in the plasma membrane (PM) increases within minutes. The increase in PM content is greater with full-length α_1C than in dCT-truncated α_1C, and requires Ser1928. The same was observed in HL-1 cells, a mouse atrium cell line natively expressing cardiac α_1C, which undergoes the proteolytic cleavage of the dCT, thus providing a native setting for exploring the effects of PKC in cardiomyocytes. Interestingly, activation of PKC preferentially increased the PM levels of full-length, L-NT α_1C. Our findings suggest that part of PKC regulation of Ca_V1.2 in the heart involves changes in channel's cellular fate. The mechanism of this PKC regulation appears to involve the C-terminus of α_1C, possibly corroborating the previously proposed role of NT-CT interactions within α_1C.