Molecular Handoffs in Nitrergic Neurotransmission

Abstract

Postsynaptic density (PSD) proteins in excitatory synapses are relatively immobile components, while there is a structured organization of mobile scaffolding proteins lying beneath the PSDs. For example, shank proteins are located further away from the membrane in the cytosolic faces of the PSDs, facing the actin cytoskeleton. The rationale of this organization may be related to important roles of these proteins as “exchange hubs” for the signaling proteins for their migration from the subcortical cytosol to the membrane. Notably, PSD95 have also been demonstrated in prejunctional nerve terminals of nitrergic neuronal varicosities traversing the gastrointestinal smooth muscles. It has been recently reported that motor proteins like myosin Va play important role in transcytosis of nNOS. In this review, the hypothesis is forwarded that nNOS delivered to subcortical cytoskeleton requires interactions with scaffolding proteins prior to docking at the membrane. This may involve significant role of “shank,” named for SRC-homology (SH3) and multiple ankyrin repeat domains, in nitric oxide synthesis. Dynein light chain LC8–nNOS from acto-myosin Va is possibly exchanged with shank, which thereafter facilitates transposition of nNOS for binding with palmitoyl-PSD95 at the nerve terminal membrane. Shank knockout mice, which present with features of autism spectrum disorders, may help delineate the role of shank in enteric nitrergic neuromuscular transmission. Deletion of shank3 in humans is a monogenic cause of autism called Phelan–McDermid syndrome. One fourth of these patients present with cyclical vomiting, which may be explained by junctionopathy resulting from shank deficit in enteric nitrergic nerve terminals.

Colligative Property of ATP: Implications for Enteric Purinergic Neuromuscular Neurotransmission

“…Evoked enteric inhibitory neuromuscular neurotransmission involves the sequential release of purines (most importantly, ATP) and the gas nitric oxide (NO), synthesized by neuronal nitric oxide synthase (nNOS) at the membranes of nerve terminals (Chaudhury et al, 2011, 2012; Chaudhury, 2014, 2015a, 2016a,b). While ATP is stored in the vesicles of the nerve terminals, NO is synthesized de novo (Chaudhury, 2016a).…”

“…The enteric inhibitory neurotransmission is represented electrophysiologically by the fast and slow IJP, mediated by the purine nucleotide ATP and NO, respectively (Chaudhury et al, 2011, 2012; Chaudhury, 2016a). While ATP is released from vesicles (Chaudhury et al, 2012), NO is synthesized by nNOS at the nerve terminal membrane (Chaudhury et al, 2009, 2011; Chaudhury, 2014). It is only scantily known whether other chemicals are co-released with ATP.…”

Myosin Va but Not nNOSα is Significantly Reduced in Jejunal Musculomotor Nerve Terminals in Diabetes Mellitus

“…Recently, evidence has been provided that mere presence of nNOS within nerve terminals is not adequate for pre-junctional NO synthesis ( 12 – 14 ). The regulation of nNOS within the nerve varicosities require multiple allosteric interactions, most notably, its positioning at PDZ-rich active zones that allow interfacing of water soluble nNOSα with membrane-bound palmitoyl-PSD95 ( 14 , 15 ).…”

Furthering the debate on the role of interstitial cells of Cajal in enteric inhibitory neuromuscular neurotransmission

“…There is no obvious direct evidence to this hypothesis. I have reported the role of prejunctional cytoskeletal force-generating proteins like myosin Va in the tandem neural release of the vesicular and nonvesicular neurotransmitters (ATP and NO, respectively) (4,7,8), which may explain the coordinative response of fast and slow IJPs on a scale of a few seconds.…”