Functional consequences of lidocaine binding to slow-inactivated sodium channels

Abstract

Na channels open upon depolarization but then enter inactivated states from which they cannot readily reopen. After brief depolarizations, native channels enter a fast inactivated state from which recovery at hyperpolarized potentials is rapid (<20 ms). Prolonged depolarization induces a slow- inactivated state that requires much longer periods for recovery (> 1 s). The slow-inactivated state therefore assumes particular importance in phatological conditions, such as ischemia, in which tissues are depolarized for prolonged periods. While use-dependent block of Na channels, the potential contribution of slow-inactivated channels has been ignored. The principal (α) subunits from skeletal muscle or brain Na channels display anomalous gating behavior when expressed in Xenopus oocytes, with a high percentage entering slow-inactivated states after brief depolarizations. This enhanced slow inactivation is eliminated by coexpressing the α subunit with the subsidiary β1 subunit. We compared the lidocaine sensitivity of α subunits expressed in the presence and absence of the β1 subunit to determine the relative contributions of fast-inactivated and slow-inactivated channel block. Coexpression of β1 inhibited the use-dependent accumulation of lidocaine block during repetitive (I-Hz) depolarizations from - 100 to - 20 mV. Therefore, the time required for recovery from inactivated channel block was measured at - 100 mV. Fast-inactivated (α + β1) channels were mostly unblocked within 1 s of repolarization; however, slow-inactivated (α alone) channels remained blocked for much longer repriming intervals (>5 s). The affinity of the slow-inactivated state for lidocaine was estimated to be 15-25 μM, versus 24 μM for the fast-inactivated state. We conclude that slow-inactivated Na channels are blocked by lidocained with an affinity comparable to that of fast-inactivated channels. A prominent functional consequence is potentiation of use-dependent block through a delay in repriming of lidocaine-bound slow-inactivated channels.