Voltage and calcium use the same molecular determinants to inactivate calcium channels

During sustained depolarization, voltage-gated Ca2+ channels progressively undergo a transition to a nonconducting, inactivated state, preventing Ca2 overload of the cell. This transition can be triggered either by the membr ane potential (voltage-dependent inactivation) or by the consecutive entry of Ca2+ (Ca2+-dependent inactivation), depending on the type of Ca2+ channe l. These two types of inactivation are suspected to arise from distinct und erlying mechanisms, relying on specific molecular sequences of the differen t pore-forming Ca2+ channel subunits. Here we report that the voltage-depen dent inactivation (of the alpha(1A) Ca2+ channel) and the Ca2+-dependent in activation (of the alpha(1C) Ca2+ channel) are similarly influenced by Ca2 channel beta subunits. The same molecular determinants of the beta subunit , and therefore the same subunit interactions, influence both types of inac tivation. These results strongly suggest that the voltage and the Ca2+-depe ndent transitions leading to channel inactivation use homologous structures of the different cu, subunits and occur through the same molecular process . A model of inactivation taking into account these new data is presented.