Truncating Mutation in the Nitric Oxide Synthase 1 Gene Is Associated With Infantile Achalasia

Shteyer, Eyal; Edvardson, Simon; Wynia-Smith, Sarah L.; Pierri, Ciro Leonardo; Zangen, Tzili; Hashavya, Saar; Begin, Michal; Barak, Yaacov; Cinamon, Yuval; Koplewitz, Benjamin Z.; Vromen, Amos; Elpeleg, Orly; Smith, Brian C.

doi:10.1053/j.gastro.2014.11.044

Cited by 37 publications

(36 citation statements)

References 18 publications

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“…The general consensus of the literature suggests that achalasia represents a family of disorders rather than a single disease with a fixed pathophysiologic profile [9,10]. The current understanding suggests that three factors determine the clinical phenotype including genetic predisposition, environmental triggers, and autoimmune myenteric plexitis [11][12][13][14]. The exact pathophysiology of the disease is not completely understood, and is beyond the scope of this review.…”

Section: Introductionmentioning

confidence: 96%

Current status of achalasia management: a review on diagnosis and treatment

Tuason

Inoue

2017

J Gastroenterol

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Background Achalasia is a rare esophageal motility disorder that is characterized by loss of peristalsis and failure of relaxation of the lower esophageal sphincter (LES), particularly during swallowing. This review focuses on the diagnosis of esophageal motility disorders as defined by the Chicago Classification ver 3.0, and presents management options with regard to per-oral endoscopic myotomy (POEM) as the treatment of choice. Methods A concise review of literature was performed for articles related to the management of achalasia, and this was contrasted with our institution's current practice. Results Achalasia is still incompletely understood, and management is focused on establishing a proper diagnosis, and relieving the obstructive symptoms. Conclusions Achalasia should be considered when dysphagia is present, and not otherwise caused by an obstruction or inflammation, and when criteria is met as per the Chicago Classification ver 3.0. Lowering LES tone and disruption of LES can be accomplished by various methods, most notably pneumatic balloon dilatation and surgical myotomy. POEM has been gaining momentum as a first line therapy for achalasia symptoms, and can be considered an important tool for motility disorders of the esophagus.

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Section: Introductionmentioning

confidence: 96%

Current status of achalasia management: a review on diagnosis and treatment

Tuason

Inoue

2017

J Gastroenterol

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“…Our findings are relevant to the pathophysiology of GI motility disorders. Slow transit constipation, gastroparesis and oesophageal achalasia are associated with diminished or excess nitrergic neurotransmission (Grover et al, ; X. Liu, Liu, Xu, Liu, & Sun, ; Shteyer et al, ). Although non‐selective AC activation (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Guerra et al, ). GI motility disorders often feature altered nNOS activity (Grover et al, ; X. Liu et al, ; Shteyer et al, ), and rodent models of GI dysmotility feature PKA hyperactivity and hypoactivity (Howe et al, ; Yu et al, ). Thus, selective modulation of AC‐coupled receptors on enteric nitrergic neurons may be clinically useful.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase A facilitates relaxation of mouse ileum via phosphorylation of neuronal nitric oxide synthase

Guerra

Bok

Lorca

et al. 2020

British J Pharmacology

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Background and Purpose: The enteric neurotransmitter nitric oxide (NO) regulates gastrointestinal motility by relaxing smooth muscle. Pharmacological cAMP induction also relaxes gastrointestinal smooth muscle, but it is uncertain whether cAMP augments or suppresses enteric NO signalling. In other organ systems, cAMP can increase neuronal NO production by stimulating protein kinase A (PKA) to phosphorylate neuronal NOS (nNOS) Serine-1412 (S1412). We hypothesized that cAMP also increases nNOS S1412 phosphorylation by PKA in enteric neurons to augment nitrergic relaxation of mouse ileum.Experimental Approach: We measured contractile force and nNOS S1412 phosphorylation in ileal rings suspended in an organ bath. We used forskolin to induce cAMP-dependent relaxation of wild type, nNOS S1412A knock-in and nNOSα-null ileal rings in the presence or absence of PKA, protein kinase B (Akt) and NOS inhibitors.Key Results: Forskolin stimulated phosphorylation of nNOS S1412 in mouse ileum.Forskolin relaxed nNOSα-null and nNOS S1412A ileal rings less than wild-type ileal rings. PKA inhibition blocked forskolin-induced nNOS phosphorylation and attenuated relaxation of wild type but not nNOS S1412A ileum. Akt inhibition did not alter nNOS phosphorylation with forskolin but did attenuate relaxation of wild type and nNOS S1412A . NOS inhibition with L-NAME eliminated the effects of PKA and Akt inhibitors on relaxation.Conclusion and Implications: PKA phosphorylation of nNOS S1412 augments forskolin-induced nitrergic ileal relaxation. The relationship between cAMP/PKA and NO is therefore synergistic in enteric nitrergic neurons. Because NO regulates gut motility, selective modulation of enteric neuronal cAMP synthesis may be useful for the treatment of gastrointestinal motility disorders. S1412A , mice doubly homozygous for the nNOS S1412A mutation and eNOS knockout; eNOS KO, mice lacking eNOS; eNOS, endothelial NOS; EPAC, exchange factor activated by cAMP; FSK, forskolin; GI, gastrointestinal;-ethyl]-5-isoquinolinesulfonamide HCl; IJP, inhibitory junction potential; KB, Krebs buffer; L-NAME, L-Nitro-L-arginine methyl ester; Myr-PKI, myristoylated PKA inhibitor peptide, residues 14-22; NANTN-[(4S)-4-amino-5-[(2-aminoethyl)-amino]-pentyl]-N 0 -nitroguanidinetris trifluoroacetate; nNOS, neuronal NOS; nNOS S1412A , mice with knock-in mutation of nNOS serine-1412 to alanine; nNOSα KO, mice lacking the first exon of nNOS; ODQ, 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one; pS1412, nNOS phosphorylated at serine-1412; S1179, serine-1179 of mouse eNOS; S1412, serine-1412 of mouse nNOS; sGC, soluble GC; TTX, tetrodotoxin; WT, wild type.

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“…A recent study in children from one family reveals that changes in the gene coding for nNOS (NOS-1) results in pediatric achalasia (80). The use of NO breakdown inhibitors such as sildenafil (a PDE5 inhibitor) is a drug therapy approach potentially useful for some of these patients (80)(81)(82). In the anal sphincter, NO induces relaxation as shown, for instance, by the efficacy of chronic anal fissure management with topical nitrites, which act as NO donors and thus favor healing by reducing sphincter tone.…”

Section: Digestive Conditions Associated With Inhibitory Neurotransmimentioning

confidence: 99%

Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

Gallego¹,

Mañé²,

Gil³

et al. 2016

Rev Esp Enferm Dig

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The enteric nervous system (ENS) is responsible for the genesis of motor patterns ensuring an appropriate intestinal transit. Enteric motor neurons are classified into afferent neurons, interneurons and motorneurons. Motorneurons are excitatory or inhibitory causing smooth muscle contraction and relaxation respectively. Muscle relaxation mechanisms are key for the understanding of physiological processes such as sphincter relaxation, gastric accommodation, or the descending phase of the peristaltic reflex. Nitric oxide (NO) and ATP or a related purine are the primary inhibitory neurotransmitters. Nitrergic neurons synthesize NO through nNOS enzyme activity. NO diffuses across the cell membrane to bind guanylyl cyclase, and then activates a number of intracellular mechanisms that ultimately result in muscle relaxation. ATP is an inhibitory neurotransmitter together with NO. The P2Y1 receptor has been identified as a the purine receptor responsible for smooth muscle relaxation. Although, probably, no clinician doubts about the significance of NO in the pathophysiology of gastrointestinal motility, the relevance of purinergic neurotransmission is apparently much lower, as ATP has not been associated with any specific motor dysfunction yet. The goal of this review is to discuss the function of both relaxation mechanisms in order to establish the physiological grounds of potential motor dysfunctions arising from impaired intestinal relaxation.

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Truncating Mutation in the Nitric Oxide Synthase 1 Gene Is Associated With Infantile Achalasia

Cited by 37 publications

References 18 publications

Current status of achalasia management: a review on diagnosis and treatment

Current status of achalasia management: a review on diagnosis and treatment

Protein kinase A facilitates relaxation of mouse ileum via phosphorylation of neuronal nitric oxide synthase

Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

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