Voltage‐dependent blockade of normal and mutant muscle sodium channels by benzylalcohol

Abstract

1 We studied the eects of benzylalcohol on heterologously expressed wild type (WT), paramyotonia congenita (R1448H) and hyperkalaemic periodic paralysis (M1360V) mutant asubunits of human skeletal muscle sodium channels. 2 Benzylalcohol blocked rested channels at 7150 mV membrane potential, with an ECR 50 of 5.3 mM in wild type, 5.1 mM in R1448H, and 6.2 mM in M1360V. When blockade was assessed at 7100 mV, the ECR 50 was reduced in R1448H (2 mM) compared with both wild type (4.3 mM; P50.01) and M1360V (4.3 mM). 3 Membrane depolarization before the test depolarization signi®cantly promoted benzylalcoholinduced sodium channel blockade. The values of K D for the fast-inactivated state derived from benzylalcohol-induced shifts in steady-state availability curves were 0.66 mM in wild type and 0.58 mM in R1448H. In the presence of slow inactivation induced by 2.5 s depolarizing prepulses, the ECI 50 for benzylalcohol-induced current inhibition was 0.59 mM in wild type and 0.53 mM in R1448H. 4 Recovery from fast inactivation was prolonged in the presence of drug in all clones. 5 Benzylalcohol induced signi®cant frequency-dependent block at stimulating frequencies of 10, 50, and 100 Hz in all clones. 6 Our results clearly show that benzylalcohol is an eective blocker of muscle sodium channels in conditions that are associated with membrane depolarization. Mutants that enter voltage-dependent inactivation at more hyperpolarized membrane potentials compared with wild type are more sensitive to inhibitory eects at the normal resting potential.

N‐Salicyloyltryptamine, a new anticonvulsant drug, acts on voltage‐dependent Na+, Ca2+, and K+ ion channels

“…Anticonvulsant agents have been reported to inhibit voltagegated ion channels, including Na þ , Ca 2 þ , and K þ channels (Funahashi et al, 2001;Kwan et al, 2001;Patten et al, 2001). The STP effect on I Na current was small, compared with data from other related drugs (Haeseler et al, 2000;Sun & Lin, 2000;Madeja et al, 2001;Xie et al, 2001). Moreover, unlike these other drugs (Gebhardt et al, 2001), inhibition by STP was not use-dependent.…”

Sodium Channel Inactivation: Molecular Determinants and Modulation

“…This was not completely achieved in equine hyperkalemic periodic paralysis (386) or paramyotonia congenita (124,438). Incidentally, two agents of possible clinical significance, the preservative 4-chloro-m-cresol and the bacteriostatic diluent benzylalcohol, have been tested on these mutants, showing typical LA behavior (167,168).…”

Tolerance to Anesthesia Depends on Synaptic Proteins

“…Previously, we have demonstrated that rapid benzyl alcohol tolerance originates in the nervous system (Ghezzi et al 2004). Like other anesthetics, benzyl alcohol has been demonstrated to inhibit channel function (Staiman and Seeman 1977;Barrantes 1993; Takadera and Ohyashiki 2008; Haeseler et al 2000). …”