TY - JOUR
T1 - Isoform-specific lidocaine block of sodium channels explained by differences in gating
AU - Nuss, H. Bradley
AU - Kambouris, Nicholas
AU - Marbán, Eduardo
AU - Tomaselli, Gordon F.
AU - Balser, Jeffrey R.
N1 - Funding Information:
This work was supported by the National Institutes of Health (R01 GM56307 to JRB, R01 HL52768 to EM, R01 HL50411 to GFT) and a grant-in-aid from the American Heart Association (Maryland Affiliate, JRB). Salary support was provided by the Clinician Scientist Award of the American Heart Association (JRB) and a NASPE fellowship grant (HBN).
PY - 2000
Y1 - 2000
N2 - When depolarized from typical resting membrane potentials (V(rest) ~ - 90 mV), cardiac sodium (Na) currents are more sensitive to local anesthetics than brain or skeletal muscle Na currents. When expressed in Xenopus oocytes, lidocaine block of hH1 (human cardiac) Na current greatly exceeded that of μ1 (rat skeletal muscle) at membrane potentials near V(rest), whereas hyperpolarization to -140 mV equalized block of the two isoforms. Because the isoform-specific tonic block roughly parallels the drug-free voltage dependence of channel availability, isoform differences in the voltage dependence of fast inactivation could underlie the differences in block. However, after a brief (50 ms) depolarizing pulse, recovery from lidocaine block is similar for the two isoforms despite marked kinetic differences in drug-free recovery, suggesting that differences in fast inactivation cannot entirely explain the isoform difference in lidocaine action. Given the strong coupling between fast inactivation and other gating processes linked to depolarization (activation, slow inactivation), we considered the possibility that isoform differences in lidocaine block are explained by differences in these other gating processes. In whole-cell recordings from HEK-293 cells, the voltage dependence of hH1 current activation was ~20 mV more negative than that of μ1. Because activation and closed-state inactivation are positively coupled, these differences in activation were sufficient to shift hH1 availability to more negative membrane potentials. A mutant channel with enhanced closed-state inactivation gating (μ1-R1441C) exhibited increased lidocaine sensitivity, emphasizing the importance of closed-state inactivation in lidocaine action. Moreover, when the depolarization was prolonged to 1 s, recovery from a 'slow' inactivated state with intermediate kinetics (I(M)) was fourfold longer in hH1 than in μ1, and recovery from lidocaine block in hH1 was similarly delayed relative to μ1. We propose that gating processes coupled to fast inactivation (activation and slow inactivation) are the key determinants of isoform-specific local anesthetic action.
AB - When depolarized from typical resting membrane potentials (V(rest) ~ - 90 mV), cardiac sodium (Na) currents are more sensitive to local anesthetics than brain or skeletal muscle Na currents. When expressed in Xenopus oocytes, lidocaine block of hH1 (human cardiac) Na current greatly exceeded that of μ1 (rat skeletal muscle) at membrane potentials near V(rest), whereas hyperpolarization to -140 mV equalized block of the two isoforms. Because the isoform-specific tonic block roughly parallels the drug-free voltage dependence of channel availability, isoform differences in the voltage dependence of fast inactivation could underlie the differences in block. However, after a brief (50 ms) depolarizing pulse, recovery from lidocaine block is similar for the two isoforms despite marked kinetic differences in drug-free recovery, suggesting that differences in fast inactivation cannot entirely explain the isoform difference in lidocaine action. Given the strong coupling between fast inactivation and other gating processes linked to depolarization (activation, slow inactivation), we considered the possibility that isoform differences in lidocaine block are explained by differences in these other gating processes. In whole-cell recordings from HEK-293 cells, the voltage dependence of hH1 current activation was ~20 mV more negative than that of μ1. Because activation and closed-state inactivation are positively coupled, these differences in activation were sufficient to shift hH1 availability to more negative membrane potentials. A mutant channel with enhanced closed-state inactivation gating (μ1-R1441C) exhibited increased lidocaine sensitivity, emphasizing the importance of closed-state inactivation in lidocaine action. Moreover, when the depolarization was prolonged to 1 s, recovery from a 'slow' inactivated state with intermediate kinetics (I(M)) was fourfold longer in hH1 than in μ1, and recovery from lidocaine block in hH1 was similarly delayed relative to μ1. We propose that gating processes coupled to fast inactivation (activation and slow inactivation) are the key determinants of isoform-specific local anesthetic action.
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U2 - 10.1016/S0006-3495(00)76585-4
DO - 10.1016/S0006-3495(00)76585-4
M3 - Article
C2 - 10620286
AN - SCOPUS:0034127170
SN - 0006-3495
VL - 78
SP - 200
EP - 210
JO - Biophysical journal
JF - Biophysical journal
IS - 1
ER -