ACTIVATION OF PROTEIN-KINASE-C PARTIALLY ALLEVIATES NORADRENALINE INHIBITION OF INSULIN-SECRETION

The sympathetic neurotransmitter noradrenaline (NA) fully inhibited both phases of glucose-stimulated insulin secretion from rat islets of Langerhans. The secretory response to the protein kinase C (PKC) activator, 4beta-phorbol myristate acetate (4betaPMA), in the absence of exogenous glucose was also abolished by NA. However, at 20 mM glucose 4betaPMA partially alleviated the inhibitory effect of NA both on insulin release and on cyclic AMP generation. Inhibition of insulin release by NA, albeit much decreased, was still observed in the presence of maximal stimulatory concentrations of both 4betaPMA and dibutyryl cyclic AMP. The relieving effect of 4betaPMA on the inhibition of insulin secretion by NA was not overcome by the competitive antagonist of cyclic AMP-dependent protein kinase, Rp-adenosine 3'.5'-cyclic phosphorothioate. Down-regulation of islet PKC activity by overnight exposure to 4betaPMA did not affect the inhibitory capacity of NA. These results suggest that NA inhibits insulin release independently of interaction with PKC, but that activation of this enzyme decreases the inhibitory effect of NA at stimulatory concentrations of glucose. This protective effect of 4betaPMA could not be attributed to a decrease in NA inhibition of cyclic AMP generation.