In vitro correction of impaired Na+-K+-ATPase in diabetic nerve by protein kinase C agonists.
Diminished Na+-K+-ATPase activity in diabetic peripheral nerve plays a central role in the early electrophysiological, metabolic, and morphological abnormalities of experimental diabetic neuropathy. The defect in Na+-K+-adenosinetriphosphatase (ATPase) regulation in diabetic nerve is linked experimentally to glucose- and sorbitol-induced depletion of nerve myo-inositol but is not fully understood at a molecular level. Therefore, regulation of nerve Na+-K+-ATPase activity by phosphoinositide-derived diacylglycerol was explored as the putative link between myo-inositol depletion and the Na+-K+-ATPase impairment responsible for slowed saltatory conduction in diabetic animal models. In vitro exposure of endoneurial preparations from alloxan-diabetic rabbits to two protein kinase C agonists, 4 beta-phorbol 12 beta-myristate 13 alpha-acetate and 1,2-(but not 1,3-) dioctanoyl-sn-glycerol, for as little as 1 min completely and specifically corrected the 40% decreased enzymatically measured ouabain-sensitive ATPase activity. Neither of these agonists affected ouabain-sensitive ATPase activity in endoneurial preparations derived from nondiabetic controls. These observations are compatible with the hypothesis that metabolites of electrically stimulated phosphoinositide turnover such as diacylglycerol acutely regulate nerve Na+-K+-ATPase activity, probably via protein kinase C, thereby tightly coupling energy-dependent Na+-K+-antiport with impulse conduction in peripheral nerve. Glucose-induced depletion of myo-inositol presumably limits phosphoinositide turnover and diacylglycerol production, thereby disrupting this putative regulatory mechanism for Na+-K+-ATPase in diabetic peripheral nerve.
Lattimer
S A
SA
Diabetes Research and Training Center, University of Michigan, Ann Arbor 48109.
Sima
A A
AA
Greene
D A
DA
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000201:enzymology* / Q000503:physiopathology; D004075:Diglycerides / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D010042:Ouabain / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011817:Rabbits; D012016:Reference Values; D012584:Sciatic Nerve / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D004075:Diglycerides; C044295:1,2-dioctanoylglycerol; D010042:Ouabain; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D013755:Tetradecanoylphorbol Acetate