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, 4 beta-phorbol myristate acetate (4 beta PMA), in the absence of exogenous glucose was also abolished by NA. However, at 20 mM glucose 4 beta PMA 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 4 beta PMA and dibutyryl cyclic AMP. The relieving effect of 4 beta PMA 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 4 beta PMA 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 4 beta PMA could not be attributed to a decrease in NA inhibition of cyclic AMP generation.
Persaud
S J
SJ
Biomedical Sciences Division, King's College London, U.K.
Jones
P M
PM
Howell
S L
SL
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007700:Kinetics; D009638:Norepinephrine / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology
D007328:Insulin; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D003994:Bucladesine; D000242:Cyclic AMP; D011493:Protein Kinase C; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine