The [Na.sup.+] channel inactivation gate is a molecular complex: a novel role of the COOH-terminal domain

Electrical activity in nerve, skeletal muscle, and heart requires finely tuned activity of voltage-gated [Na.sup.+] channels that open and then enter a nonconducting inactivated state upon depolarization. Inactivation occurs when the gate, the cytoplasmic loop linking domains III and IV of the [alpha] subunit, occludes the open pore. Subtle destabilization of inactivation by mutation is causally associated with diverse human disease. Here we show for the first time that the inactivation gate is a molecular complex consisting of the III-IV loop and the COOH ter-minus (C-T), which is necessary to stabilize the closed gate and minimize channel reopening. When this interaction is disrupted by mutation, inactivation is destabilized allowing a small, but important, fraction of channels to reopen, conduct inward current, and delay cellular repolarization. Thus, our results demonstrate for the first time that physiologically crucial stabilization of inactivation of the [Na.sup.+] channel requires complex interactions of intracellular structures and indicate a novel structural role of the C-T domain in this process. KEY WORDS: inactivation * long QT syndrome * sodium channel * structure * heart