Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.

Abstract

Voltage-gated Na+ channels are the molecular targets of local anesthetics, class I antiarrhythmic drugs, and some anticonvulsants. These chemically diverse drugs inhibit Na+ channels with complex voltage-and frequencydependent properties that reflect preferential drug binding to open and inactivated channel states. The site-directed mutations F1764A and Y1771A in transmembrane segment IVS6 of type IIA Na+ channel ai subunits dramatically reduce the affinity of inactivated channels for the local anesthetic etidocaine. In this study, we show that these mutations also greatly reduce the sensitivity of Na+ channels to state-dependent block by the class Ib antiarrhythmic drug lidocaine and the anticonvulsant phenytoin and, to a lesser extent, reduce the sensitivity to block by the class Ta and Ic antiarrhythmic drugs quinidine and flecainide. For lidocaine and phenytoin, which bind preferentially to inactivated Na+ channels, the mutation F1764A reduced the affinity for binding to the inactivated state 24.5-fold and 8.3-fold, respectively, while Y1771A had smaller effects. For quinidine and flecainide, which bind preferentially to the open Na+ channels, the mutations F1764A and Y1771A reduced the affinity for binding to the open state 2-to 3-fold. Thus, F1764 and Y1771 are common molecular determinants of state-dependent binding of diverse drugs including lidocaine, phenytoin, flecainide, and quinidine, suggesting that these drugs interact with a common receptor site. However, the different magnitude of the effects of these mutations on binding of the individual drugs indicates that they interact in an overlapping, but nonidentical, manner with a common receptor site. These results further define the contributions of F1764 and Y1771 to a complex drug receptor site in the pore of Na+ channels.Voltage-gated Na+ channels are responsible for the initiation and propagation of action potentials in both nerve and muscle cells (1, 2). The main structural component of Na+ channels is the 260-kDa a subunit, which forms the Na+ selective pore and other structures necessary for channel function. In mammalian Na+ channels, the a subunit associates with one or two smaller auxiliary subunits designated 131 and ,32. Na+ channel function is regulated by voltage-dependent transitions among three sets of functionally distinct conformational states. At hyperpolarized membrane potentials, most Na+ channels are in closed resting states. In response to membrane depolarization, channels rapidly convert to an open state that conducts Na+ ions and then to a nonconducting, inactivated state. The opening and subsequent inactivation of Na+ channels results in a transient inward current that inactivates within a few milliseconds.Class I antiarrhythmic drugs such as lidocaine, quinidine, and flecainide (3, 4) as well as some anticonvulsants including phenytoin and carbamazepine (5) act by inhibiting ionic currents through voltage-gated Na+ channels. Tertiary amine local anesthetics, like procaine and etidocaine, which are chemically related...

Contribution of the tetrodotoxin-resistant voltage-gated sodium channel Na V 1.9 to sensory transmission and nociceptive behavior

“…2D). This sensitivity to lidocaine was similar to that reported for the resting-state block of the TTX-resistant current in rat DRGs (24) and of several recombinant Na V 1 channel subtypes (25,26), suggesting that the pharmacology of Na V 1.9 may be similar to that of other Na V 1 subtypes.…”

Preferential block of inactivation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel

“…As in their report, the accuracy of these values may be limited because of the inadequate concentration range. The inactivated-channel block by etidocaine is considerably more effective than the resting-channel block, by a factor of >10 (Ragsdale et al, 1994;Ragsdale et al, 1996). Such strong inactivatedchannel block is found in most local anesthetics.…”

Potent block of inactivation-deficient Na+ channels by n-3 polyunsaturated fatty acids

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