Desensitisation does not selectively alter sodium channels

Abstract

WHEN depolarising drugs are applied to the endplate region of skeletal muscle fibres, the postjunctional membrane undergoes a rapid increase in ionic conductance. This increased permeability, largely for Na⁺ and K⁺, is slowly reversed if the agonist application is sustained. The gradual diminuition of response to agonist is due to endplate desensitisation¹. Many factors influencing desensitisation have been described, but the molecular mechanisms responsible for the development of desensitisation remain unknown. Two fundamental types of mechanisms have been postulated to explain the phenomenon of desensitisation^2–6. In the first, desensitisation is viewed as resulting from an alteration in the chemical receptor or binding site. The second type of mechanism suggests that desensitisation results from an alteration at some extrareceptor site such as that controlling the ionic channel in the endplate membrane. Kuba and Koketsu⁷ have shown that the reversal potential for acetylcholine was shifted to more negative values at desensitised end-plates. They argued that this change was due to a selective decrease in G_Na and therefore supported the view that an extra-receptor mechanism was important in the development of desensitisation. In contrast Koester⁸ found no significant alteration in the reversal potential at desensitised endplates. In view of these conflicting observations we have re-investigated the question of whether there is or is not a selective alteration in endplate conductance during desensitisation. We report here that desensitisation does not selectively alter sodium channels.