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J Biol Chem, Vol. 274, Issue 9, 5483-5490, February 26, 1999

Voltage and Calcium Use the Same Molecular Determinants to Inactivate Calcium Channels

From the Centre de Recherches de Biochimie Macromoléculaire, CNRS UPR 1086, 1919 Route de Mende, F34293 Montpellier, France

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 membrane potential (voltage-dependent inactivation) or by the consecutive entry of Ca²⁺ (Ca²⁺-dependent inactivation), depending on the type of Ca²⁺ channel. These two types of inactivation are suspected to arise from distinct underlying mechanisms, relying on specific molecular sequences of the different pore-forming Ca²⁺ channel subunits. Here we report that the voltage-dependent inactivation (of the _1A Ca²⁺ channel) and the Ca²⁺-dependent inactivation (of the _1C Ca²⁺ channel) are similarly influenced by Ca²⁺ channel  subunits. The same molecular determinants of the  subunit, and therefore the same subunit interactions, influence both types of inactivation. These results strongly suggest that the voltage and the Ca²⁺-dependent transitions leading to channel inactivation use homologous structures of the different ₁ subunits and occur through the same molecular process. A model of inactivation taking into account these new data is presented.

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