Neurite outgrowth in dorsal root ganglia induced by islet neogenesis-associated protein peptide involves protein kinase A activation.
Islet neogenesis-associated protein (INGAP) peptide is a candidate therapeutic for diabetes and corrects sensory dysfunction in experimental diabetes in mice. In this study, we investigated the mechanism of action by which INGAP peptide promotes neurite outgrowth in sensory neurons of the dorsal root ganglia. Treatment of dorsal root ganglia primary dispersed cultures with INGAP peptide led to the displacement of fluorescently labeled forskolin from adenylate cyclase, the cyclic AMP-generating enzyme that has been implicated in neuritogenesis. The addition of forskolin or dibutyryl cyclic AMP enhanced the effects of INGAP peptide on neurite outgrowth in dorsal root ganglia explant cultures. Furthermore, pharmacological inhibition of adenylate cyclase with SQ22,536 or of protein kinase A with H89 or KT5720 significantly reduced the neurite-promoting effects of INGAP peptide. These results suggest that INGAP peptide-induced neurite outgrowth in the dorsal root ganglia partially involves cyclic AMP-dependent activation of protein kinase A.
Tam
Joseph
J
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Rosenberg
Lawrence
L
Maysinger
Dusica
D
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology*; D003952:Diagnostic Imaging / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments / Q000494:pharmacology*; D013997:Time Factors
D016207:Cytokines; D004791:Enzyme Inhibitors; C500438:INGAP peptide; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments; C000612141:REG3A protein, human; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases