title: The good and bad effects of cysteine S-nitrosylation and tyrosine nitration upon insulin exocytosis: a balancing act.
abstract: As understanding of the mechanisms driving and regulating insulin secretion from pancreatic beta cells grows, there is increasing and compelling evidence that nitric oxide (•NO) and other closely-related reactive nitrogen species (RNS) play important roles in this exocytic process. •NO and associated RNS, in particular peroxynitrite, possess the capability to effect signals across both intracellular and extracellular compartments in rapid fashion, affording extraordinary signaling potential. It is well established that nitric oxide signals through activation of guanylate cyclase-mediated production of cyclic GMP. The intricate intracellular redox environment, however, lends credence to the possibility that •NO and peroxynitrite could interact with a wider variety of biological targets, with two leading mechanisms involving 1) Snitrosylation of cysteine, and 2) nitration of tyrosine residues comprised within a variety of proteins. Efforts aimed at delineating the specific roles of •NO and peroxynitrite in regulated insulin secretion indicate that a highly-complex and nuanced system exists, with evidence that •NO and peroxynitrite can contribute in both positive and negative regulatory ways in beta cells. Furthermore, the ultimate biochemical outcome within beta cells, whether to compensate and recover from a given stress, or not, is likely a summation of contributory signals and redox status. Such seeming regulatory dichotomy provides ample opportunity for these mechanisms to serve both physiological and pathophysiologic roles in onset and progression of diabetes. This review focuses attention upon recent accumulating evidence pointing to roles for nitric oxide induced post-translational modifications in the normal regulation as well as the dysfunction of beta cell insulin exocytosis.
authors.affiliation: Department of Pediatrics, Herman B Wells Center, Basic Diabetes Group, Indianapolis, IN, USA. gwiseman@iupui.edu
authors.forename: Dean A
authors.initials: DA
authors.lastname: Wiseman
authors.forename: Debbie C
authors.initials: DC
authors.lastname: Thurmond
mesh_terms: D017209:Apoptosis; D006152:Cyclic GMP / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism* / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects*; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D014443:Tyrosine; D006152:Cyclic GMP; D003545:Cysteine