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About the Authors:
Arun Chaudhury
Contributed equally to this work with: Arun Chaudhury, Vivian Cristofaro
Affiliation: Divisions of Surgery, VA Boston Healthcare System and Harvard Medical School, Boston, Massachusetts, United States of America
Vivian Cristofaro
Contributed equally to this work with: Arun Chaudhury, Vivian Cristofaro
Affiliation: Division of Urology, VA Boston Healthcare System and Harvard Medical School, Boston, Massachusetts, United States of America
Josephine A. Carew
Affiliation: Division of Medicine, VA Boston Healthcare System and Harvard Medical School, Boston, Massachusetts, United States of America
Raj K. Goyal
Affiliation: Division of Medicine, VA Boston Healthcare System and Harvard Medical School, Boston, Massachusetts, United States of America
Maryrose P. Sullivan
* E-mail: [email protected]
Affiliation: Division of Urology, VA Boston Healthcare System and Harvard Medical School, Boston, Massachusetts, United States of America
Introduction
Nitric oxide (NO) produced by splice variants of the enzyme neuronal nitric oxide synthase (nNOS) has been shown to be a major inhibitory neurotransmitter at smooth muscle neuromuscular junctions. Smooth muscle relaxation facilitated by NO released from nerve varicosities subserves essential physiological functions in many organ systems that are as diverse as gastric motility and penile erection [1]–[4]. In these prototypical examples of nitrergic neurotransmission, impaired relaxation has been shown to cause, respectively, a variety of gastrointestinal motility disorders including loss of gastric accommodation [5] and erectile dysfunction [6].
During nitrergic neurotransmission, NO is synthesized de novo and released on demand from nitrergic varicosities [7]. Failed nitrergic neurotransmission may result from an absence or critical reduction in the amount of nNOS or impairment of its catalytic function. Many factors determine the catalytic activity of nNOS including dimerization [8]–[9], and its interaction with regulatory proteins and calcium ions [10]–[12]. Moreover, the subcellular localization of nNOS also regulates its catalytic activity [13]–[15]. Within enteric varicosities, membrane localization of nNOSα has been shown to be necessary for optimal NO synthesis [15]. nNOSα has an N-terminal PDZ domain which binds the PDZ domains of PSD95, a membrane bound scaffolding protein concentrated at ‘active zones’ [8], [15]. These zones are characterized by a supra-molecular assembly of nNOSα dimers, close to the source of calcium surge during an action potential, thus optimizing NO synthesis and ensuring focal release of NO [14]–[15].
While nNOS tethering to the membrane has been well studied,...