Post-translational regulation of neuronal nitric oxide synthase: implications for sympathoexcitatory states

Abstract

Introduction Nitric oxide (NO) synthesized via neuronal nitric oxide synthase (nNOS) plays a significant role in regulation/modulation of autonomic control of circulation. Various pathological states are associated with diminished nNOS expression and blunted autonomic effects of NO in the central nervous system (CNS) including heart failure, hypertension, diabetes mellitus, chronic renal failure etc. Therefore, elucidation of the molecular mechanism/s involved in dysregulation of nNOS is essential to understand the pathogenesis of increased sympathoexcitation in these diseased states. Areas Covered nNOS is a highly regulated enzyme, being regulated at transcriptional and posttranslational levels via protein-protein interactions and modifications viz. phosphorylation, ubiquitination, and sumoylation. The enzyme activity of nNOS also depends on the optimal concentration of substrate, cofactors and association with regulatory proteins. This review focuses on the posttranslational regulation of nNOS in the context of normal and diseased states within the CNS. Expert Opinion Gaining insight into the mechanism/s involved in the regulation of nNOS would provide novel strategies for manipulating nNOS directed therapeutic modalities in the future, including catalytically active dimer stabilization and protein-protein interactions with intracellular protein effectors. Ultimately, this is expected to provide tools to improve autonomic dysregulation in various diseases such as heart failure, hypertension, and diabetes.

Dual role of nitrergic neurotransmission in the bed nucleus of the stria terminalis in controlling cardiovascular responses to emotional stress in rats

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Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

“…Thus, extensive unbiased and enhanced sampling MD simulations could provide additional insight, at the atomic level, into the numerous questions about the inner structural organization of NOSred, such as: i) What are the mechanisms of NOSred activity modulation by the regulatory elements? ii) Which structural changes are induced by PTMs in this domain (including phosphorylation of several serines in cNOSs, phosphorylation of Thr 495 and S -glutathionylation of Cys 689 and Cys 908 in eNOS [ 81 , [104] , [105] , [106] ])? iii) Are the regulatory mechanisms of the NOS isoforms different?…”

Nitrosative Stress Is Associated with Dopaminergic Dysfunction in the HIV-1 Transgenic Rat

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