Some Aspects of the Mechanisms Involved in Adrenergic Neurotransmission

5OME ASPECTS OF THE MECHANISMS INVOLVED IN ADRENERGIC NEUROTRANSMISSION U. S. VON EULER* I.Introduction The development ofknowledge in the field ofchemical neurotransmission follows in many respects the general course observed in many other scientific areas. This applies to the first conceptual suggestions [i] as well as to the performance ofingenious experiments designed to prove the hypothesis [2, 3] and the identificationofthetransmitter [4, 5]. Laterfollowed systematic research into various detail mechanisms at the subcellular and the molecular level aiming at a better understanding ofthe phenomena. As in so many other cases, various factors have tended to delay the progress, and for future students the history of the development in this fieldhardly offers any dramatic features clearly distinguishing itfrom other areas. The present stage can perhaps be characterized as a kind ofimpasse, strongly in need of a breakthrough. This still seems distant, perhaps because it involves a number ofproblems concerning fundamental processes in living material, such as mechanisms oftransport through membranes, formation of membranes and organelles, binding to "receptors," concerted enzymatic reactions, and similar events. To put it in other terms, the specific problem ofadrenergic neurotransmission now has approached the frontier line ofprogress in general biological research and will presumably have to await the developments in this larger field before it can proceed further on its own. II.Intraneural Distribution and Transmitter Homeostasis After the identification of the transmitter with noradrenaline (NA) [4, 5] and the development of suitable quantitative assay methods, its * Professor of physiology, Karolinska Institute, Stockholm, Sweden. This paper was presented at the twentieth anniversary commemoration symposium ofthe Oklahoma Medical Research Foundation in Oklahoma City, November, 1967, and will be published in the Proceedings. It is printed here with the permission ofthe Foundation. 79 distribution in nerves and organs could be systematically investigated. These studies showed that the NA content varied greatly, from about io Mgm./gram in some organs, such as the vas deferens and the vesicular gland in some animals, to less than one one-hundredth ofthis amount in other organs, such as skeletal muscle and testicles. On the other hand, the NA content of one and the same organ was found to be quite constant, normally. The adrenergic nerve fibers themselves, such as bovine splenic nerves, containabout 10-15 pgm./gram ofNA. Theamounts ofNA in the organs proved to be strongly correlated with the number of adrenergic nerve fibers running to the organ, which, though typical for any one organ, varies greatly between different organs. The relative constancy ofthe NA content per unit weight oftissue, even assuming constancy of innervation, clearly requires that the adrenergic neuron contain a fixed amount of transmitter. This transmitter homeostasis was a valuable clue to the concept of specific storage, which will be discussed below. The specificity ofthe binding of the transmitter to adrenergic axons was first demonstrated by the finding that section and denervation ofthe adrenergic fibers are accompanied by a fall ofthe neurohumor content ofthe organ to very low values [6]> but as regeneration occurs the NA content rises again [7]. In agreement with this, nerve-free organs, like the umbilical vessels or the placenta, lack NA. III. Nerve-ending Morphology and Storage Granules A prerequisite, or at least a valuable support, for the understanding of the mechanism of adrenergic neurotransmission is knowledge about the morphological features of the nerve endings. The existence of regularly recurring swellings of the terminal axons, first described by Hiilarp [8], and their visualization by the fluorescence method of Falck and Hiilarp some fifteen years later [9], have suggested that these structures are intimately connected with neurotransmission. Strangely enough, the adrenaline, serving as transmitter in the frog, does not appear to be bound in the same way,judging from histochemical experiments [10]. Another approach to the problem was based on comparisons of the relative amounts ofNA in the splenic nerves and in the spleen itself, which indicated a one-hundred- to one-thousandfold accumulation of the trans80 U. S. von Euler · Adrenergic Neurotransmission Perspectives in Biology and Medicine · Autumn 1968 mitter somewhere in the neuron, presumably in the terminal parts. Such a strong concentration would be hard to understand unless the transmitter were bound in some protected storage form, most likely in some...