Gasotransmitters in pregnancy: from conception to uterine involution†

Guerra, Damian D.; Hurt, K. Joseph

doi:10.1093/biolre/ioz038

Cited by 31 publications

(32 citation statements)

References 335 publications

(366 reference statements)

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“…Depolarization of nitrergic enteric neurons leads to voltagedependent calcium (Ca 2+ ) entry, activation of calmodulin (CaM), and increased NO production by nNOS. NO stimulates soluble guanylate cyclase (sGC) to produce cGMP, which activates protein kinase G (PKG) to promote smooth muscle relaxation (12,13). Elevated neuronal intracellular [Ca 2+ ] is therefore a major stimulus for nitrergic relaxation (14).…”

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confidence: 99%

Akt phosphorylation of neuronal nitric oxide synthase regulates gastrointestinal motility in mouse ileum

Guerra

Bok

Vyas

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Nitric oxide (NO) is a major inhibitory neurotransmitter that mediates nonadrenergic noncholinergic (NANC) signaling. Neuronal NO synthase (nNOS) is activated by Ca2+/calmodulin to produce NO, which causes smooth muscle relaxation to regulate physiologic tone. nNOS serine1412 (S1412) phosphorylation may reduce the activating Ca2+ requirement and sustain NO production. We developed and characterized a nonphosphorylatable nNOSS1412A knock-in mouse and evaluated its enteric neurotransmission and gastrointestinal (GI) motility to understand the physiologic significance of nNOS S1412 phosphorylation. Electrical field stimulation (EFS) of wild-type (WT) mouse ileum induced nNOS S1412 phosphorylation that was blocked by tetrodotoxin and by inhibitors of the protein kinase Akt but not by PKA inhibitors. Low-frequency depolarization increased nNOS S1412 phosphorylation and relaxed WT ileum but only partially relaxed nNOSS1412A ileum. At higher frequencies, nNOS S1412 had no effect. nNOSS1412A ileum expressed less phosphodiesterase-5 and was more sensitive to relaxation by exogenous NO. Under non-NANC conditions, peristalsis and segmentation were faster in the nNOSS1412A ileum. Together these findings show that neuronal depolarization stimulates enteric nNOS phosphorylation by Akt to promote normal GI motility. Thus, phosphorylation of nNOS S1412 is a significant regulatory mechanism for nitrergic neurotransmission in the gut.

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confidence: 99%

Akt phosphorylation of neuronal nitric oxide synthase regulates gastrointestinal motility in mouse ileum

Guerra

Bok

Vyas

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Section: Introductionmentioning

confidence: 99%

“…Estrogen (17β-estradiol; E 2 ) regulates uterine artery blood flow (UBF) via the gasotransmitter nitric oxide (NO) [ 1 ]. Following menses and during pregnancy, rising E 2 levels activate endothelial NO synthase (eNOS) to produce NO from arginine [ 1 , 2 ]. NO stimulates the soluble guanylate cyclase (sGC)-protein kinase G (PKG) pathway, which promotes relaxation of vascular myocytes and causes vasodilation and increased blood flow [ [3] , [4] , [5] , [6] , [7] ].…”

Section: Introductionmentioning

confidence: 99%

“…In some situations, E 2 replacement therapy can exacerbate post-menopausal cardiovascular disease [ 14 ]. This may be due to oxidative stress promoting eNOS uncoupling to favor O 2 − synthesis and NO oxidation to cytotoxic peroxynitrite [ 1 , 14 , 15 ]. It is unclear whether E 2 affects the uterine artery redox state or if redox conditions regulate NO dependent increases in UBF.…”

Section: Introductionmentioning

confidence: 99%

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Cystathionine γ-lyase promotes estrogen-stimulated uterine artery blood flow via glutathione homeostasis

et al. 2021

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“…Nitric oxide (NO) is a NANC neurotransmitter that relaxes smooth muscle via the soluble guanylate cyclase (sGC)‐cGMP‐PKG pathway in myocytes (D. D. Guerra & Hurt, ; Lefebvre, Smits, & Timmermans, ). The primary NO source in the gastrointestinal (GI) tract is neuronal NOS (nNOS), expressed in inhibitory myenteric neurons (Mang, Truempler, Erbelding, & Kilbinger, ).…”

Section: Introductionmentioning

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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Gasotransmitters in pregnancy: from conception to uterine involution†

Cited by 31 publications

References 335 publications

Akt phosphorylation of neuronal nitric oxide synthase regulates gastrointestinal motility in mouse ileum

Akt phosphorylation of neuronal nitric oxide synthase regulates gastrointestinal motility in mouse ileum

Cystathionine γ-lyase promotes estrogen-stimulated uterine artery blood flow via glutathione homeostasis

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

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