Ca(v)β surface charged residues contribute to the regulation of neuronal calcium channels

Voltage-gated calcium channels are essential regulators of brain function where they support depolarization-induced calcium entry into neurons. They consist of a pore-forming subunit (Ca(v)α(1)) that requires co-assembly with ancillary subunits to ensure proper functioning of the channel. Among these ancillary subunits, the Ca(v)β plays an essential role in regulating surface expression and gating of the channels. This regulation requires the direct binding of Ca(v)β onto Ca(v)α(1) and is mediated by the alpha interacting domain (AID) within the Ca(v)α(1) subunit and the α binding pocket (ABP) within the Ca(v)β subunit. However, additional interactions between Ca(v)α(1) and Ca(v)β have been proposed. In this study, we analyzed the importance of Ca(v)β(3) surface charged residues in the regulation of Ca(v)2.1 channels. Using alanine-scanning mutagenesis combined with electrophysiological recordings we identified several amino acids within the Ca(v)β(3) subunit that contribute to the gating of the channel. These findings add to the notion that additional contacts besides the main AID/ABP interaction may occur to fine-tune the expression and properties of the channel. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-021-00887-3.