ACCELERATED DESENSITIZATION OF NICOTINIC RECEPTOR CHANNELS AND ITS DEPENDENCE ON EXTRACELLULAR CALCIUM IN ISOLATED SKELETAL-MUSCLES OF STREPTOZOTOCIN-DIABETIC MICE

1 To elucidate the influence of the diabetic state on desensitization of nicotinic acetylcholine (ACh) receptor channels, we investigated th e time course of the decrease in amplitude of ACh potentials elicited by iontophoretic application to isolated diaphragm muscle of streptozo tocin-diabetic mice. We also investigated time- and extracellular Ca2-dependent changes in the channel opening frequency of ACh-activated c hannel currents and the involvement of protein kinases by use of the c ell-attached patch clamp technique in single skeletal muscle cells. 2 When ACh potentials were evoked at 10 Hz, the decline in trains of ACh potentials was accelerated in the diabetic state. 3 The time-dependen t decrease in the channel opening frequency of diabetic muscle cells w as greatly accelerated compared with normal cells in 2.5 mM Ca2+ mediu m. 4 This accelerated decrease in channel opening frequency was restor ed by pretreatment with a protein kinase C inhibitor, staurosporine (1 0 nM) but neither a protein kinase A inhibitor, H-89 (3 mu M) nor a ca lmodulin kinase II inhibitor, KN-62 (5 mu M) were able to restore the fall in opening frequency. 5 These results demonstrate that in the dia betic state the desensitization of nicotinic ACh receptor channels may be greatly accelerated by activating protein kinase C, which is cause d by an increase in the amount of available intracellular Ca2+.