1. To elucidate the influence of the diabetic state on desensitization of nicotinic
acetylcholine (ACh) receptor channels, we investigated the time course of the
decrease in amplitude of ACh potentials elicited by iontophoretic application to
isolated diaphragm muscle of streptozotocin-diabetic mice. We also investigated
time- and extracellular Ca(2+)-dependent changes in the channel opening
frequency of ACh-activated channel currents and the involvement of protein
kinases by use of the cell-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-dependent
decrease in the channel opening frequency of diabetic muscle cells was greatly
accelerated compared with normal cells in 2.5 mM Ca2+ medium. 4. This
accelerated decrease in channel opening frequency was restored by pretreatment
with a protein kinase C inhibitor, staurosporine (10 nM) but neither a protein
kinase A inhibitor, H-89 (3 microM) nor a calmodulin kinase II inhibitor, KN-62 (5
microM) were able to restore the fall in opening frequency. 5. These results
demonstrate that in the diabetic state the desensitization of nicotinic ACh receptor
channels may be greatly accelerated by activating protein kinase C, which is
caused by an increase in the amount of available intracellular Ca2+.
Xanya Sofra Weiss
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