SIGNAL-TRANSDUCTION ALTERATIONS IN PERIPHERAL-NERVES FROM STREPTOZOTOCIN-INDUCED DIABETIC RATS

We have previously determined the presence of muscarinic receptors and the expression of several G proteins in homogenates and myelin fracti ons from rat sciatic nerves, In the present study we investigated whet her changes in several signal transduction pathways in peripheral nerv es might be responsible for some of the biochemical abnormalities (e,g ,, phosphoinositide metabolism) present in sciatic nerves from strepto zotocin-induced diabetic rats, Sciatic nerves from 5 week diabetic rat s that were prelabelled with [H-3]-myo-inositol displayed a significan t increase in the basal release of inositol mono- and bis-phosphate, w hile carbamylcholine-stimulated release was significantly smaller, Bas al- and forskolin-stimulated adenylyl cyclase activity was significant ly decreased in sciatic nerve homogenates from diabetic animals. Howev er, we were unable to detect any significant differences in the levels of cAMP in intact nerves or in nerve segments that were incubated in the presence or absence of forskolin, ADP-ribosylation experiments sho wed that in sciatic nerves from experimentally diabetic rats there was a significant increase in the ADP-ribosylation catalyzed by cholera a nd pertussis toxins, Measurements of the levels of alpha-subunits of G proteins revealed that the expression of G(q/11)alpha, G(s) alpha, an d G(i-3)alpha was increased by 30 to 50%, These results indicate that during the course of experimental diabetes, peripheral nerves exhibit an abnormal production of inositol phosphates and cAMP, together with an abnormal expression and/or function of G proteins, One of the conse quences of such alterations is the diminished release of inositol phos phates triggered by muscarinic agonists in diabetic sciatic nerves. (C ) 1995 Wiley-Liss, Inc.