NEURONAL METABOLISM 



1823 



was discovered a quarter of a century ago (42). 

 Depolarization of conductive tissue was believed to be 

 metabolically passive, involving pre-existing electro- 

 chemical gradients, while repolarization was a process 

 requiring energy. The source of energy was thought 

 to be largely from carbohydrate metabolism via ATP, 

 but there was evidence that noncarbohydrate sub- 

 strates were involved, particularly during activity 

 (39, 42, 44). With the advent of the theory that nerve 

 conduction was directly related to the transport of 

 sodium and potassium (55), interest was renewed in 

 the problem of selective ionic accumulation and the 

 metabolic factors accompanying it. Excitability of 

 conductive tissue is dependent upon the ability to 

 maintain a high internal potassium concentration 

 against a strong electrochemical gradient. Metabolic 

 energy was presumed to be necessary for maintaining 

 potassium influx as well as the efflux of the sodium 

 entering during activity (55). 



In studies with the giant axon of Sepia loligo it has 

 been found that metabolic inhibitors such as cyanide, 

 azidc and dinitrophenol, as well as cooling to 1 °C, 

 will block both sodium extrusion and potassium 

 uptake in the resting state, while dinitrophenol had 

 only a slight effect on the rapid movements of sodium 

 during the passage of impulses (56). Hodgkin & 

 Keynes (56) concluded from such observations that 

 the 'permeability system,' which allows ionic transport 

 across an electrochemical gradient during activity, is 

 not metabolically dependent as is the "secretory 

 mechanism' which is operative only during the 

 recovery phase. The movement of ions during ac- 

 tivity, which is some 2,000 times greater than is 

 possible at rest (56), is a process requiring only an 

 increase in permeability allowing sodium and 

 potassium to move down electrochemical gradients. 



Another mechanism for the action potential 

 attributes the net influx of sodium to a transient 

 inhibition of the metabolic process extruding sodium 

 (48). Such a view is consistent with the observation 

 that the major pathway of energy production is 

 inhibited during excitation in nerve fibers (8, 9). The 

 increase in respiratory activity occurring during 

 excitation is not coupled to increased phosphoryla- 

 tion, so that a true •uncoupling' of oxidation and 

 phosphorylation may lie taking place (8). Such a 

 mechanism for sodium entry during activity would 

 obviate the difficulties incumbent in the concept of 

 'membrane permeability' (;ii). There is evidence 

 from many sources to indicate that excitation is 

 accompanied by decreased energv output; in brain 

 slices (82, 83), brain mitochondria (9) and sartorius 



muscle (64, in), the uptake of orthophosphate-P 3 ' 2 by 

 frog nerves is inhibited during excitation (8). A 

 considerable decrease in the K. Xa ratio, and in K 42 

 turnover of rat brain and muscle mitochondria has 

 been observed with electrical excitation as well as 

 dinitrophenol (5). These observations, along with the 

 finding that a depletion of intramitochondrial 

 potassium results in decreased phosphorylation 

 support the thesis that K-Na transport and phos- 

 phorylation are closely related (8, 56). 



Inhibition of synthetic reactions during increased 

 activity may also be the mechanism whereby ATP is 

 rapidly degraded. It does not appear unlikely that 

 catabolic reactions are generally held in check by 

 anabolic ones, and only after die latter are suppressed 

 will the former become accelerated. The main- 

 tenance of intracellular K in brain slices and retina is 

 dependent, not only on phosphorylation, or an energy- 

 source, but also upon the presence of glutamic acid 

 (112). It is not at all clear what the role of glutamic 

 acid is in nerve function, although it is involved in a 

 diverse number of interesting chemical reactions. 

 Besides bring a source of metabolic energy , glutamate 

 is also involved in the depletion of ATP according to 

 the following reaction : 



glutamate + ATP + XH, «=> glutamine + ADP + P 



This reaction may be of importance in the removal 

 of the highly toxic ammonia formed as a result of 

 activity (96). Recently, y-aminobutyric acid formed 

 b\ the decarboxylation of glutamate has been shown 

 to have an inhibitory effect (anticholinergic) on 

 neural activity and may be acting as a neurohumoral 

 agent (26, 51). Of particular significance is the fact 

 that glutamic acid decarboxylase increases rather 

 abruptly during die period of neuronal maturation 

 (<i;l Another possible function of intracellular 

 glutamic acid is in the regulation of the relative 

 amounts of lice and bound acetylcholine (114). The 

 diverse functional roles of glutamate and its deriva- 

 tives are highly suggestive of its importance in neural 

 function, although the precise links and mechanisms 

 have yet to be elucidated. 



In connection with the problem of phosphorylation 

 during activity, there are two points to discuss; one 

 concerned with a possible mechanism by which 

 electrical currents can alter phosphorylation, and 

 the other with the problem of whether excitability 

 is a process directly dependent on energy- production 

 or an active process of sodium extrusion. One ex- 

 planation for the mechanism by which electrical 



