Low intracellular pH and chemical agents slow inactivation gating in sodium channels of muscle

Abstract

Excitation of nerve or muscle requires an orderly opening and closing of molecular pores, the ionic channels, in the plasma membrane. During the action potential, Na channels are opened (activated) by the advancing wave of depolarisation, contributing a pulse of inward sodium current, and then are closed again (inactivated) by the continued depolarisation. As one approach both to obtaining molecular information on the Na channel and towards further defining the recently discovered kinetic interactions of the inactivation and activation gating steps, we have surveyed here the effects of chemical agents reported to slow or prevent Na channel inactivation. We find that many of the agents studied by others on invertebrate giant axons or vertebrate nerve act on our frog skeletal muscle preparation. In addition, we have discovered that simply lowering the intracellular pH nearly eliminates inactivation. The activation mechanism seems to resist modification.

Calcium‐independent increase of transmitter release at frog end‐plate by trinitrobenzene sulphonic acid.

“…Externally and internally applied TNBS acts on the sodium channel located on the plasma membrane of the frog muscle fibre in completely different ways. It accelerates inactivation when applied extracellularly (Cahalan & Pappone, 1981), while it blocks inactivation when applied intracellularly (Nonner, Spalding & Hille, 1980). TNBS almost certainly acts, at least in the first stage of the reaction, on the external surface of the presynaptic membrane.…”

Removal of sodium channel inactivation in squid axon by the oxidant chloramine-T.

“…Cleavage alone, however, only indicates the presence, and not the functional importance, of these residues . Subsequent experiments with lysineand arginine-modifying reagents and with agents that mimic peptides containing arginine Kirsch et al, 1980;Lo and Shrager, 1982;Nonner et al, 1980) have demonstrated that an arginine residue was probably present and was an integral part of the inactivation mechanism.…”

Effects of intracellular pH on calcium‐activated potassium channels in rabbit tracheal smooth muscle.

“…Intracellular acidification delays inactivation of the Na+ current in frog skeletal muscle (Nonner, Spalding & Hille, 1980). In cardiac muscle, Ca2+ currents are inhibited by lowering pHi (Vogel & Sperelakis, 1977;Irisawa & Sato, 1986;Kaibara & Kameyama, 1988).…”