The Effect of Calcium on the Desensitization of Membrane Receptors at the Neuromuscular Junction

Abstract

Desensitization, as represented by the progressive decline in the electromotive effects of depolarizing agents at the neuromuscular junction, was studied by observing the time course of changes in effective transmembrane resistance during the prolonged application of 0.27 mM carbamylcholine to the postjunctional region of frog skeletal muscle fibers. The effective transmembrane resistance was measured by means of two intracellular microelectrodes implanted in the junctional region of single muscle fibers. When carbamylcholine was applied to the muscle there was an immediate decrease in the effective membrane resistance followed by a slower return toward control values which was identified as the phase of desensitization. When the calcium concentration was increased from 0 to 10 mM there was an approximately sevenfold increase in the rate of desensitization. On the other hand, an increase in the concentration of sodium from 28 to 120 mM caused a slowing of the rate of desensitization. Even in muscles depolarized by potassium sulfate, calcium increased the rate of desensitization while high concentrations of potassium tended to prolong the process. Some mechanisms by which calcium might exert these effects are discussed.

Imaging of intracellular calcium during desensitization of nicotinic acetylcholine receptors of rat chromaffin cells

“…Although the long lasting nature of [Ca 2+ ] i increase by nicotine is compatible with the ®rst hypothesis, initially put forward by Manthey (1966), the second possibility accords with recent biochemical and electrophysiological observations. In fact, molecular biology studies have shown that desensitization is an intrinsic property of ligand-gated ionotropic receptors (see review by Lena & Changeux, 1993) and that is can be modulated by intracellular second messengers via phosphorylation of certain receptor subunits (Levitan, 1994).…”

“…Early work on nicotinic AChRs of skeletal muscle ®bres has suggested that [Ca 2+ ] o is important in the control of onset and extent of desensitization (Manthey, 1966;Magazanik & Vyskocil, 1970), although it has subsequently been shown that desensitization still takes place in the absence of [Ca 2+ ] o and is reduced by an injection of EGTA into the postsynaptic ®bre (Miledi, 1980). Unlike muscle nicotinic AChRs, neuronal-type receptors of chroma n cells are highly permeable to Ca 2+ (Vernino et al, 1994) which is thus potentially capable of modulating the process of desensitization.…”

“…In the case of nicotinic acetylcholine receptors (AChRs) early work showed that their desensitization was accelerated by high extracellular Ca 2+ levels ([Ca 2+ ] o ) (Manthey, 1966;Magazanik & Vyskocil, 1970), whereas subsequent studies have suggested that raised intracellular Ca 2+ concentration ([Ca 2+ ] i ) is actually the important factor to facilitate desensitization on muscle (Miledi, 1980;Chestnut, 1983). Progress in this ®eld has been aided by the observation that desensitization of nicotinic AChRs is a heterogeneous process comprising fast and slow phases (Feltz & Trautmann, 1982;MacOnochie & Knight, 1992), only the latter one being modulated by [Ca 2+ ] i (Cachelin & Colquhoun, 1989).…”

Effect of Ionophore X‐537a on Desensitization Rate and Tension Development in Potassium‐depolarized Muscle Fibres

“…In the continued presence of recently that this site is located on the internal surface agonist, the conductance gradually returns toward the of the postjunctional membrane and therefore is pre-activation state as 'desensitization' occurs distinct from the agonist-recognition site on the (Thesleff, 1955). Manthey (1966) has shown that external surface of this membrane (Nastuk & Parsons, raising the external calcium concentration accelerates 1970; Cochrane & Parsons, 1972;Parsons, Schnitzler & Cochrane, 1974). This view would be greatly…”

The effects of external Ca++ and Mg++ on the voltage sensitivity of desensitization in Electrophorus electroplaques.

“…This decrease in permeability marks the onset of desensitization which has been described for the frog neuromuscular junction (Fatt, 1950;Thesleff, 1955;Katz and Thesleff, 1957), and occurs in the electroplaque at rates comparable to those observed in the frog when agonist is iontophoretically (del Castillo and Webb, 1977) or bath-applied (Lester, et al, 1975). At the frog neuromuscular junction the rate of onset of desensitization is affected by agonist type and concentration, extracellular ion concentrations and membrane voltage (Thesleff, 1955;Katz and Thesleff, 1957;Manthey, 1966Manthey, , 1970Rang and Ritter, 1970;Nastuk and Parsons, 1970;Magazanik andVyskocil, 1970, 1975;Parsons et al, 1974;Adams, 1975).…”