Binding of Gαo N Terminus Is Responsible for the Voltage-resistant Inhibition of α1A (P/Q-type, Cav2.1) Ca2+ Channels

Abstract G-protein-mediated inhibition of presynaptic voltage-dependent Ca2+ channels is comprised of voltage-dependent and -resistant components. The former is caused by a direct interaction of Ca2+channel α1 subunits with Gβγ, whereas the latter has not been characterized well. Here, we show that the N terminus of Gαo is critical for the interaction with the C terminus of the α1A channel subunit, and that the binding induces the voltage-resistant inhibition. An α1A C-terminal peptide, an antiserum raised against Gαo N terminus, and a Gαo N-terminal peptide all attenuated the voltage-resistant inhibition of α1A currents. Furthermore, the N terminus of Gαo bound to the C terminus of α1A in vitro, which was prevented either by the α1A channel C-terminal or GαoN-terminal peptide. Although the C-terminal domain of the α1B channel showed similar ability in the binding with Gαo N terminus, the above mentioned treatments were ineffective in the α1B channel current. These findings demonstrate that the voltage-resistant inhibition of the P/Q-type, α1A channel is caused by the interaction between the C-terminal domain of Ca2+ channel α1A subunit and the N-terminal region of Gαo.