Relationship of calcium and phosphates to bioelectric phenomena in the excitatory membrane.

Abstract

PERSPECTIVES IN BIOLOGY AND MEDICINE Volume IX · Number l · Autumn 1965 RELATIONSHIP OF CALCIUM AND PHOSPHATES TO BIOELECTRIC PHENOMENA IN THE EXCITATORY MEMBRANE L. G. ABOOD* AND NORMAN W. GABEL\ I.Introduction Some thirty-five years ago Ralph Gerard was grappling with problems pertaining to the role ofphosphates and intermediary metabolism in nerve conduction, at a time when neurochemistry and electrophysiology were just emerging as separate disciplines. In an important review [i] he emphasized the need for understanding the relationship ofATP and energy metabolism in terms of the action potential and other bioelectric phenomena . He consistently stressed forhis students the importance ofrelating chemical events to neural function, while encouraging investigators from varied disciplines to collaborate and exchange ideas on neurobiological problems. His conviction that organic phosphates must play a significant role in excitatory phenomena is onlyjust beginning to find experimental verification. II.Calcium and Membrane Permeability The role ofCa2+ in the regulation ofmembrane permeability had been suspected almost a century ago [2]; but not until the last two decades has attention been given to the possible mechanisms whereby Ca2+ influences the macromolecular structure ofmembranes. Renewed interest was stimulated by the finding ofFrankenhaeuser and Hodgkin [3] that the degree of * Center for Brain Research, University ofRochester, Rochester, New York 14627. t University of Illinois College of Medicine, Dept. of Psychiatry, P.O. 6998, Chicago, Illinois 60680. membrane depolarization was a function ofthe extracellular Ca*+ concentration in the squid axon. It was Ringer [2] who originally focused attention on the bivalent character ofCa2+ and its ability to link adjacent acidic macromolecules within the membrane in order to regulate permeability and, thereby, excitability. Evidence continues to accumulate in support of the argument that a change in degree ofassociation of membrane Ca2+ is a critical factor in depolarization. Ofprimary importance to an understanding ofthe role of Ca2+ in excitatory processes is a knowledge ofthe chemical nature of the membrane Ca2+ and the factors controlling its exchange. A fundamental argument of this report is that phosphate ions play a major role in the regulation ofCa2+ exchange. III. Phosphate Exchange and Depolarization For the past fifteen years our (L. G. A.) interest has been focused on the relationship of phosphorus to bioelectric phenomena in excitable tissues [4-6]. Such studies, which are ofparticular significance in relation to the role of Ca2+ in membrane permeability, can be summarized as follows: (a) Depolarization, whetherproduced byhigh externalK+, Ca2+ displacement , or electrically, produces an increased efflux ofPi (orthophosphate) and ATP from excitatory tissues, (b) This efflux is a function ofthe degree ofdepolarization, (c) Depolarization results in an inhibition of Pi influx and, secondarily, incorporation of Pi into ATP. (d) The impairment of Pi uptakecloselyparallelsthedecreasingmembranepotentialresultingfrom an increased concentration ofexternal K+ (see Fig. 1). (e) From a determination ofthermodynamic constants for P efflux and P incorporation, it was inferred that the two processes were somewhat related and that they involved both enzymatically driven and nonenzymatic processes, (f) The resting potential appears to be dependent upon the availability of membrane ATP (ATP is compartmentalized in the cell [5]) so that when the total amount decreases to less than 75 per cent ofthe normal value, the potential rapidly diminishes [6]. The apparent conclusion ofthese findings was that the systems involved in the transfer ofphosphorus across the membrane were also involved in membrane depolarization. It was also inferred that the phosphate exchange or transport was directly related to the role of Ca2+ in the regulation of membrane permeability. It was proposed that Ca2+ and ATP formed a L. G. Abood and Norman W. Gabel · Bioelectric Phenomena in Excitatory Membrane Perspectives in Biology and Medicine · Autumn 196$ complex with macromolecular components in the membrane and that the dissociation ofthis complex occurred during depolarization [5]. IV. Calcium Association with Phosphates There are a number of possible mechanisms for explaining how Ca2+ removal from the membrane results in the loss of internal Pi and ATP. One possibility is that there is a generalized increase in permeability following Ca2+ removal or displacement from the membrane. According to this concept, Ca2+imparts structural rigidity and organization to the membrane by virtue ofits ability to form coordination complexes and poorly dissociable salts with lipids, proteins, and polysaccharides comprising the membrane structure...