Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 301, Issue 3, Pages G498-G507Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00164.2011
Keywords
DBA mice; LC8; enteric nerves; nitrergic inhibitory junction potential; myosin Va; active nNOS; inactive nNOS
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [DK-062867]
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Nitrergic neurotransmission at the smooth muscle neuromuscular junctions requires nitric oxide (NO) release that is dependent on the transport and docking of neuronal NO synthase (nNOS) alpha to the membrane of nerve terminals. However, the mechanism of translocation of nNOS alpha in actin-rich varicosities is unknown. We report here that the processive motor protein myosin Va is necessary for nitrergic neurotransmission. In wild-type mice, nNOS alpha-stained enteric varicosities colocalized with myosin Va and its tail constituent light chain 8 (LC8). In situ proximity ligation assay showed close association among nNOS alpha, myosin Va, and LC8. nNOS alpha was associated with varicosity membrane. Varicosities showed nitric oxide production upon stimulation with KCl. Intracellular microelectrode studies showed nitrergic IJP and smooth muscle hyperpolarizing responses to NO donor diethylenetriamine-NO (DNO). In contrast, enteric varicosities from myosin Va-deficient DBA (for dilute, brown, non-agouti) mice showed near absence of myosin Va but normal nNOS alpha and LC8. Membrane-bound nNOS alpha was not detectable, and the varicosities showed reduced NO production. Intracellular recordings in DBA mice showed reduced nitrergic IJPs but normal hyperpolarizing response to DNO. The nitrergic slow IJP was 9.1 +/- 0.7 mV in the wild-type controls and 3.4 +/- 0.3 mV in the DBA mice (P < 0.0001). Deficiency of myosin Va resulted in loss of nitrergic neuromuscular neurotransmission despite normal presence of nNOS alpha in the varicosities. These studies reveal the critical importance of myosin Va in nitrergic neurotransmission by facilitating transport of nNOS alpha to the varicosity membrane.
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