i8->4 



HANDBOOK OF PHYSIOLOGY 



\1 I RopHYSIOLOGY III 



currents can affect metabolism is by means of iono- 

 phoresis in such a manner as to alter the effective 

 concentration of an essential ion at an enzyme 

 surface (9). A depletion of intramitochonchial 

 potassium during excitation may be sufficient to 

 bring about an inhibition of phosphorylation or, 

 perhaps, a critical displacement of other ions essential 

 to phosphorylation, such as magnesium or DPN. 

 Another possibility is that excitation induces certain 

 reversible structural alterations within the mito- 

 chondria which are sullieienl to disturb the delicate 

 balance of organization essential to phosphorylation 

 (8, 9). The work of Tobias and others (19, 113) 

 and Hill (52) leaves little doubt that significant 

 structural changes are concomitant with nerve con- 

 duction; and since these changes seem to involve 

 particulates, it is not inconceivable that mitochondrial 

 metabolism is altered. 



Recentlv, extremely interesting changes have been 

 observed in neurons cultured in vitro under the 

 influence of neurotropic drugs and during electrical 

 Stimulation (41; personal communication). Electrical 

 excitation and pentylenetetrazol caused the nucleus 

 to appear enlarged while accelerating movements of 

 iIk cytoplasmic granules and nucleolus. In addition, 

 the neuronal processes become more motile, may 

 shorten and become beaded with large clumps of 

 granules. Depressant drugs, on the other hand, result 

 in an almost complete disappearance of cytoplasmic 

 granules, with complete reappearance in 15 min. 

 Whether or not the granules actually disappear and 

 are resynthesized de novo is not certain, but the con- 

 clusion is inescapable that mitochondria and other 

 granules are responsive to variations in neuronal 

 acti\ it> . 



I here is Still another point to diseuss in regard to 

 the failure to observe increased phosphorylation 

 during excitation, namely, the possibility that forms 

 ol 'high energy' bonds other than phosphates may be 

 exhibiting an increased turnover. An exergonic 

 reaction of considerable magnitude is that involving 



transacelv lation ol thiol esters such .is in the following 



react 



AMP + acyl-Co AS + IT 



+2. ATP + CoA Nil + acyl compound 



l tie hydrolysis of acyl imidazoles is also an exergonic 

 n .11 Hon ( 1 09, 1 16), 



.11 etyl < loA -I imidazole 



<=± acetyl-imidazole t ( loA 

 acetyl-Im + P ?=t acetyl-P I imidazole 



Although attempts to demonstrate the enzymatic 

 acetylation of histidinc, carnosine and other bio- 

 chemically important imidazoles have been so far 

 unsuccessful, the possibility that such reactions do 

 occur certainly exists. 



The intracellular accumulation of cations has been 

 attributed to a diverse number of cellular components, 

 including various structural components. In an 

 effort to account for the intracellular accumulation of 

 potassium and sodium on the basis of soluble anions, 

 such as amino acids and phosphates, a sulphydryl 

 compound, isothionic, was discovered in squid 

 axoplasm which presumably made up this 'anion 

 deficit' (70). The "fixed-charge hypothesis' of Ling 

 (76) has endeavored to explain the selective accumula- 

 tion of potassium on the basis that the smaller hy- 

 drated potassium ion has a greater adsorption 

 energy than sodium and is, thereby, more likely to 

 combine with 'fixed charges.' Although protein 

 molecules in the alkaline range have many free 

 anionic sites, many other structural components, such 

 as nucleic acids, phosphatides and even mucopoly- 

 saccharides could be involved (cf. 1 ). In addition to 

 possessing available anionic sites, many of these 

 components are polymers capable of altering their 

 structural configuration and thereby the availability 

 of binding sites. The degree of cross linkages in 

 polystyrene resins, for example, greatly influences the 

 selective binding of potassium (76). Ion transport 

 during excitatory activity may be accompanied by 

 reversible alterations in the polymeric configuration 

 of such substances (1). 



As is evident from the foregoing discussion, as well 

 as from the historv of the chemistry of muscle con- 

 traction, the question of function is inextricablv 

 linked to the chemical events of the neuron. If the 

 fundamental event in nerve conduction should prove 

 to be explainable on the basis of the sodium-potassium 

 flux concept, future effort should be directed towards 

 .\i\ elucidation of the metabolic and physicochemical 

 events regulating ion exchange. Such concepts as ion 

 binding, perineabilitv and active transport are 

 sti ictlv dynamic ones involving a complex of chemical 

 processes all the way from energetic transformation 

 to the intramolecular rearrangements within proteins 

 and other polymeric substances within the cell. The 

 study of the neuron demands an intermingling of all 

 the available techniques of the natural sciences, and 

 .in\ severe compartmentalization ol disciplines would 

 be particularly misleading with regard to the neuron. 



\. uronal chemistry, at least as far as concerns our 





