TY - JOUR
T1 - Mechanistic link between lidocaine block and inactivation probed by outer pore mutations in the rat μ1 skeletal muscle sodium channel
AU - Kambouris, Nicholas G.
AU - Hastings, Laura A.
AU - Stepanovic, Svetlana
AU - Marban, Eduardo
AU - Tomaselli, Gordon F.
AU - Balser, Jeffrey R.
PY - 1998/11/1
Y1 - 1998/11/1
N2 - 1. Mutations that disrupt Na+ channel fast inactivation attenuate lidocaine (lignocaine)-induced use dependence; however, the pharmacological role of slower inactivation processes remains unclear. In Xenopus oocytes, tryptophan substitution in the outer pore of the rat skeletal muscle channel (μ1-W402) alters partitioning among fast- and slow-inactivated states. We therefore examined the effects of W402 mutations on lidocaine block. 2. Recovery from inactivation exhibited three kinetic components (I(F), fast; I(M), intermediate; I(S), slow). The effects of W402A and W402S on I(F) and I(S) differed, but both mutants (with or without β1 subunit coexpression) decreased the amplitude of I(M). In wild-type channels, lidocaine imposed a delayed recovery component with intermediate kinetics, and use-dependent block was attenuated in both W402A and W402S. 3. To examine the pharmacological role of I(S) relative to I(M), drug-exposed β1-coexpressed channels were subjected to 2 min depolarizations. Lidocaine had no effect on sodium current (I(Na)) after a 1 s hyperpolarization interval that allowed recovery from I(M) but not I(S), suggesting that lidocaine affinity for I(S) is low. 4. Both W402 mutations reduced occupancy of I(M) in drug-free conditions, and also induced resistance to use-dependent block. We propose that lidocaine-induced use dependence may involve an allosteric conformational change in the outer pore.
AB - 1. Mutations that disrupt Na+ channel fast inactivation attenuate lidocaine (lignocaine)-induced use dependence; however, the pharmacological role of slower inactivation processes remains unclear. In Xenopus oocytes, tryptophan substitution in the outer pore of the rat skeletal muscle channel (μ1-W402) alters partitioning among fast- and slow-inactivated states. We therefore examined the effects of W402 mutations on lidocaine block. 2. Recovery from inactivation exhibited three kinetic components (I(F), fast; I(M), intermediate; I(S), slow). The effects of W402A and W402S on I(F) and I(S) differed, but both mutants (with or without β1 subunit coexpression) decreased the amplitude of I(M). In wild-type channels, lidocaine imposed a delayed recovery component with intermediate kinetics, and use-dependent block was attenuated in both W402A and W402S. 3. To examine the pharmacological role of I(S) relative to I(M), drug-exposed β1-coexpressed channels were subjected to 2 min depolarizations. Lidocaine had no effect on sodium current (I(Na)) after a 1 s hyperpolarization interval that allowed recovery from I(M) but not I(S), suggesting that lidocaine affinity for I(S) is low. 4. Both W402 mutations reduced occupancy of I(M) in drug-free conditions, and also induced resistance to use-dependent block. We propose that lidocaine-induced use dependence may involve an allosteric conformational change in the outer pore.
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U2 - 10.1111/j.1469-7793.1998.693bd.x
DO - 10.1111/j.1469-7793.1998.693bd.x
M3 - Article
C2 - 9769414
AN - SCOPUS:0032212560
SN - 0022-3751
VL - 512
SP - 693
EP - 705
JO - Journal of Physiology
JF - Journal of Physiology
IS - 3
ER -