It is commonly believed that acetylcholine (ACh) is the physiological transmitter of sympathetic nerve impulses at the adrenal medulla. The reasons are the following: the sympathetic nerve fibres that innervate the adrenal medullary cells are developmental homologues of the preganglionic fibres elsewhere in the sympathetic nervous system which are known to be cholinergic; on stimulation of the adrenal nerves an acetylcholine-like substance is released from the adrenal gland (Feldberg, Minz & Tsudzimura, 1934); ACh is a powerful stimulant of adrenal medullary secretion; and finally, transmission at the adrenal medulla is affected by a variety of drugs in much the same way as these drugs affect transmission at the established sites of cholinergic transmission at sympathetic ganglionic synapses.The purpose of the present experiments was to study the mechanism by which ACh brings about adrenal medullary secretion and, as a first approach, to observe how the response of the gland to ACh might be influenced by changes in the ionic composition of the extracellular environment. Our experiments show that the excitant action of ACh on the adrenal medulla is dependent on the presence of calcium, and suggest that ACh evokes adrenal medullary secretion by causing calcium ions to penetrate the adrenal medullary cells.
Although evidence has existed for many years that the sympathetic nerves innervating the adrenal medulla are cholinergic, it is only quite recently that a number of observations have been made which together provide a possible explanation of how acetylcholine, the chemical mediator, stimulates the chromaffin cells to secrete the catecholamines adrenaline and noradrenaline. The recent evidence has come from studies on perfused adrenal glands showing that the stimulant effect of acetylcholine involves some calcium-dependent process (Douglas & Rubin, 1961). Thus acetylcholine was found to be without effect on catecholamine release when calcium was omitted from the perfusion fluid, and its efficacy in releasing catecholamines was directly related to the extracellular calcium concentration over a wide range. Moreover, calcium itself, in conditions known to increase the permeability of cell membranes, proved to be an adequate stimulus for catecholamine secretion. These findings, considered along with the known ability of acetylcholine to increase membrane permeability at some other sites in the body where it also acts as a chemical transmitter, led us to suggest that acetylcholine evokes adrenal medullary secretion through some action on the chromaffin cell membranes leading to an increased uptake or influx of calcium ions, and that calcium ions provide the immediate stimulus for the release of catecholamines. Support for this idea has come from more recent studies showing that the rate of 45Ca uptake by the adrenal medulla is indeed increased by ACh (Douglas & Poisner, 1961, 1962.The present experiments have been carried out to examine further the role of calcium and other inorganic ions in the process we have termed 'stimulus-secretion coupling' at the adrenal medulla.
Several receptors for neurotransmitters, hormones and growth factors cause accelerated phosphodiesteratic breakdown of polyphosphoinositides when activated. One of the soluble products of this reaction, inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) is thought to act as a second messenger signalling the release of Ca2+ from intracellular stores. In support of this hypothesis, several studies have shown that Ins(1,4,5)P3 releases sequestered Ca2+ from permeable cells and microsomes. On the basis of certain structural requirements for Ca2+-releasing activity by inositol phosphates, it has been postulated that Ins(1,4,5)P3 acts by binding to a specific intracellular receptor, probably on a component of the endoplasmic reticulum. Here we report that 32P-Ins(1,4,5)P3 binds to a specific saturable site in permeabilized guinea pig hepatocytes and rabbit neutrophils, and that the properties of this binding site suggest that it is the physiological receptor for Ins(1,4,5)P3.
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