Functional consequences of lidocaine binding to slow-inactivated sodium channels

71Citations
Citations of this article
23Readers
Mendeley users who have this article in their library.

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.

Cite

CITATION STYLE

APA

Balser, J. R., Nuss, H. B., Romashko, D. N., Marban, E., & Tomaselli, G. F. (1996). Functional consequences of lidocaine binding to slow-inactivated sodium channels. Journal of General Physiology, 107(5), 643–658. https://doi.org/10.1085/jgp.107.5.643

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free