Regulation of voltage-gated calcium channels by proteolysis

Voltage gated calcium channels (VGCCs) are multi-subunit membrane proteins present in a variety of tissues and control many essential physiological processes. Due to their vital importance, VGCCs are regulated by a myriad of proteins and signaling pathways. Here we review the literature on the regulation of VGCCs by proteolysis of the pore-forming α1 subunit, Ca(v)α(1). This form of regulation modulates channel function and degradation and affects cellular gene expression and excitability. L-type Ca(2+) channels are proteolyzed in two ways, depending on tissue localization. In the heart and skeletal muscle, the distal C-terminus of Ca(v)α(1) is cleaved and acts as an autoinhibitor when it reassociates with the proximal C-terminus. Relief of this autoinhibition underlies the β-adrenergic stimulation-induced enhancement of cardiac and skeletal muscle calcium currents, part of the "fight or flight" response. Proteolysis of the distal C-terminus of L-type channels also occurs in the brain and is probably catalyzed by a calpain-like protease. In some brain regions, the entire C-terminus of L-type Ca(2+) channels can be cleaved by an unknown protease and translocates to the nucleus acting as a transcription factor. The distal C-terminus of P/Q-channel Ca(v)α(1) is also proteolyzed and translocates to the nucleus. Truncated forms of the PQ-channel Ca(v)α(1) are produced by many disease-causing mutations and interfere with the function of full-length channels. Truncated forms of N-type channel Ca(v)α(1), generated by mutagenesis, affect the expression of full-length channels. New forms of proteolysis of VGCC subunits remain to be discovered and may represent a fruitful area of VGCC research.