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) S-nitrosylation 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.

Mitochondrial Ion Channels/Transporters as Sensors and Regulators of Cellular Redox Signaling

“…Redox signaling has also gained recognition for its role in mediating diverse tissue-specific cellular functions across a wide range of cell types. For instance, redox signaling regulates muscle contraction/relaxation (145,155,169,178), insulin secretion from pancreatic beta cells (191), metabolic cycles in liver (137), self-renewal and differentiation in stem cells (98), and T-cell homeostasis (67,100,120).…”

Studies of the regulated assembly of SNARE complexes in adipocytes

“…This is particularly intriguing, given the potential for dysfunction under conditions of nitrosative stress associated with some clinical pathologies. Sx4 is modified by S-nitrosylation in β-cell lines in response to short-term treatment with inflammatory cytokines, and this correlates with dysfunctional glucose-stimulated insulin secretion [37]. Such studies reinforce the notion that the machinery that regulates membrane trafficking may offer unique nodes of therapeutic intervention.…”

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

“…Yet, we cannot rule out the involvement of others toxic compounds, particularly during NAFPD progression. Indeed, some studies suggest a possible causal relationship between NAFLD/ NAFPD-related disorders with chronic intermittent hypoxia elicited by obstructive sleep apnea [165,166], bacterial endotoxin [167][168][169], glyceraldehyde [170], methylglyoxal [171][172][173], advanced glycation end products (AGE)s [174], receptor for advanced glycation end products (RAGE) [175], nitric oxide/peroxynitrite [176], and lipid peroxidation end products [177,178].…”