Bioelectric Potential and Cellular Metabolism: Effect of 2,4-Dinitrophenol on the Membrane Potential of Muscle Fibers

BIOELECTRIC POTENTIAL AND CELLULAR METABOUSM EFFECT OF 2,4-DINlTROPHENOL ON THE MEMBRANE POTENTIAL OF MUSCLE FIBERS K. KOKETSU* An interesting topic which has begun to attract both neurophysiologists and neurochemists is the one concerned with the relationship between cellular metabolism and nervous function. Dr. Gerard in his classical review [i] clearly defined the nature of the problems relating energy metabolism to neural function, and thereby established the groundwork for subsequent research in the field. Although the bioelectric potential must be dependent more or less on cellular metabolism, little is known about which ofthe processes involved in the maintenance ofthe resting potential or the production of the action potential is linked to cellular metabolism. The most obvious experimental test ofthis question is to examine the action ofmetabolic inhibitors on the resting and action potentials ofexcitable cells. In this respect, 2,4-dinitrophenol (DNP) is one of the more useful drugs, as this is known to be a powerful inhibitor ofenergetic metabolism. In order to discuss the effect of a metabolic inhibitor on the bioelectric potential, it is essential to have a basic concept ofthe mechanism underlying the development ofthe potential changes across the cellular membrane in the resting and active states ofexcitable tissues. Unfortunately, however, there seems to be no convincing hypothesis or theory dealing with the mechanism ofion movements across the membrane during the resting and active states. The concept which is most widely accepted, particularly among electrophysiologists, is that ofthe ionic theory [2-4]. According to this theory, an asymmetric distribution ofK and Cl ions across * Research Laboratories, Department ofPsychiatry, University ofIllinois College ofMedicine, Chicago, Illinois. This research was supported by the Institute ofNeurological Diseases and Blindness , National Institutes ofHealth Grant NB 01650. 54 K. Koketsu · Bioelectric Potential and Cellular Metabolism Perspectives in Biology and Medicine · Autumn 1965 the membrane is established by Donnan's distribution resulting from the existence ofimpermeable anions in the cytoplasm. It has been assumed in this theory that the resting potential is a kind of diffusion potential expressed by Goldman's equation [5], and the immediate energy source for setting up this type ofpotential is the thermal energy ofthe ions in the extra- and intracellular fluid. It is further assumed that a sequence ofprocesses associated with the production ofthe action potential is a kind of physical phenomenon which can take place without consuming any significant chemical energy. Thus, energetic metabolism is directly linked only to the processes ofthe Na-pump and K-uptake by which the resting potential is maintained, and the changes in the membrane permeability responsible for excitation can take place as long as the resting potential is maintained normal. A number ofexperimental results [2-4], particularly those observed with the squid giant axon under the effect ofDNP [6, 7], support such a concept. The situation seems to be somewhat complicated, however, in the case of frog's skeletal muscle fibers, where the resting potential is markedly decreased by DNP and other metabolic inhibitors [8-11] without any significant change in the active transport ofions across the membrane [12, 13]. The present paper will describe further experiments dealing with the effect ofDNP on the resting and action potentials offrog's skeletal muscle fibers [14-16]. Experimental results seem to provide some information for discussing two fundamentalproblems: (1) whether there is any correlation between the changes in the bioelectric potential and those in energetic metabolism of muscle cells; and (2) whether or not the changes in the bioelectric potential, caused by DNP, can be explained onthe basis ofthe ionic theory. Experimental Data and Discussion ?. Effect ofDNP on the restingpotential and intracellular Kconcentration.— As seen in Figure 1, the membrane offrog's skeletal muscle fibers is markedly depolarized in Ringer's solution containing DNP in concentrations of 0.01-1 mM [14]. A similar effect on the resting potential ofskeletal muscle fibers has been observed with other metabolic inhibitors [8, 10, 11]. It must be noted here that the effect ofDNP on the resting potential ofsquid giant axon is very small; the resting potential is decreased slowly, but no faster than might be expected from a gradual depletion ofthe internal K 55 concentration [6]. The marked depolarization ofthe skeletal muscle membrane by the...