A study of the ‘desensitization’ produced by acetylcholine at the motor end‐plate

Abstract

It has been accepted for many years that acetylcholine (ACh) undergoes two kinds of reactions at the motor end-plate: it combines with a receptor molecule (which leads to an increase of ion permeability in the end-plate membrane), and it combines with a hydrolytic enzyme situated side-by-side with the receptor. Both reactions probably proceed in two steps and involve the formation of unstable intermediate compounds before the hydrolysis, or the depolarizing reaction, occurs (see, for example, Augustinsson, 1948; Ariens, 1954;Stephenson, 1956; del Castillo & Katz, 1957 b However, the picture of two simple, parallel events at the end-plate fails to account for an important secondary effect ofACh and its depolarizing analogues, namely the profound desensitization which develops when the drug concentration is maintained for a sufficiently long time. Recent experiments (Thesleff, 1955) have shown that the neuromuscular block produced by ACh and by its stable counterparts (C10, succinylcholine) is due mainly to desensitization, that is, a condition in which the end-plate has become refractory to depolarizing agents, and from which it recovers only slowly after complete withdrawal of the drug. It has been suggested that this change arises from gradual transformation of the drug-receptor compound into an inactive form. In order to obtain some information on the kinetics of desensitization and recovery processes, we have used the ionophoretic micromethods described by Nastuk (1953) and by del Castillo & Katz (1955a). It seemed possible that the time course of the events might come well within the practical range of this method, and the results described in this paper have borne out this expectation.

Desensitization of neuronal nicotinic receptors

“…1(B)]; and extensive desensitization could be achieved even at low concentrations of ACh. As realized by Katz and Thesleff (1957), these features are only readily interpretable in terms of a cyclical (as opposed to a linear) model of desensitization. In their favored scheme [ Fig.…”

“…Katz and Thesleff (1957) provided the first comprehensive description of desensitization for muscle nAChRs. Their detailed kinetic analysis of both desensitization onset and recovery revealed several fundamental features of this phenomenon that placed restrictions on its mechanistic basis.…”

“…As first noted by Katz and Thesleff (1957), nonlinear summation of responses at low doses of agonist is indicative of multiple agonist binding steps, and Katz and Thesleff (1957). (B) An extended Katz and Thesleff scheme that includes two sequential agonist binding steps and two desensitized states, of intermediate (I) and high (D) affinities.…”

“…The onset is both time-and concentration-dependent [ Fig. 1(A); Katz and Thesleff, 1957]. At the microscopic level, this process reflects the time-dependent accumulation of receptors in longlived nonconducting states (e.g., Sakmann et al, 1980;Colquhoun and Ogden, 1988).…”

“…Moreover, because purified nAChRs reconstituted in lipid bilayers can undergo desensitization, this process must be intrinsic to the receptor protein (see Ochoa et al, 1989)-although, as we will discuss, it can be modified by a variety of other cellular agents and exogenous signals (Huganir and Greengard, 1990). After removal of agonist the receptor can recover back to its initial resting state; however, although desensitization is potentially fully reversible, complete recovery need not occur-particularly following chronic agonist treatment (Katz and Thesleff, 1957). Incomplete recovery may reflect long-lasting accumulation of receptors in one or more desensitized states or indeed may be due to the permanent loss of functional channels (Simasko et al, 1986;Boyd, 1987;Lukas, 1991; although see Buisson and Bertrand, 2002).…”