PMC:7573190 / 28809-32525
Annnotations
{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7573190","sourcedb":"PMC","sourceid":"7573190","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7573190","text":"Nitric oxide acts through S-nitrosylation\nNitric oxide through S-nitrosylation of glucokinase (at cysteine-371) and syntaxin 4 (at cysteine-141) facilitates GSIS (Rizzo and Piston, 2003[105]; Wiseman et al., 2011[134]; Kruszelnicka, 2014[65]; Seckinger et al., 2018[113]). Using quantitative imaging of multicolor fluorescent proteins fused to glucokinase, it has been demonstrated that the dynamic association of glucokinase with secretory granules is modulated by NO (Rizzo and Piston, 2003[105]). Indeed, insulin is found to stimulate NO production leading to S-nitrosylation of glucokinase in cultured β-cells (βTC3 cells); moreover, inhibition of NOS disrupts glucokinase association with secretory granules and glucokinase conformation (Rizzo and Piston, 2003[105]). It has been demonstrated that elevated glucose and S-nitrosylation, both induce the same high-activity glucokinase conformational state I in βTC3 cells (Seckinger et al., 2018[113]). Ultimately, attachment of a nuclear localization signal sequence to NOS in βTC3 cells drives glucokinase to the nucleus in addition to its normal cytoplasmic and granule targeting (Rizzo and Piston, 2003[105]). These data suggest that the regulation of glucokinase localization and activity in pancreatic β-cells is directly related to NO production and that the association of glucokinase with secretory granules occurs through its interaction with NOS.\nThe SNARE proteins are post-translationally modified by NO, which in turn impacts vesicle exocytosis; NO-stimulated vesicle exocytosis was found to be mediated by activation of the core complex proteins involved in docking and fusion of the vesicles (Meffert et al., 1996[89]). In experiments using recombinant proteins, NO donors (sodium nitroprusside (SNP), acidified sodium nitrite, S-nitrosoglutathione, S-nitrosocysteine and a saturated solution of NO gas) increase formation of the VAMP/SNAP-25/syntaxin 1a core complex and inhibit the binding of n-sec1 to syntaxin 1a (Meffert et al., 1996[89]); these NO donors lower the EC50 of VAMP binding to SNAP-25/syntaxin (Meffert et al., 1996[89]). In addition, S-nitrosylation of syntaxin 1a (at cysteine-145) seems to be a molecular switch to disrupt Munc18-1 binding to the closed conformation of syntaxin 1a, thereby facilitating its engagement with the membrane fusion machinery (Palmer et al., 2008[98]). Taken together, these activities are predicted to promote vesicle docking/fusion.\nAt present, only the t-SNARE protein syntaxin 4 has been shown to be specifically S-nitrosylated in pancreatic β-cells; once S-nitrosylated, this event facilitates GSIS (Wiseman et al., 2011[134]; Kruszelnicka, 2014[65]). Interestingly, while syntaxin 1 is a target of S-nitrosylation in neuronal cells and tissues (Pongrac et al., 2007[102]; Palmer et al., 2008[98]), it is not modified in response to glucose in the pancreatic β-cells, demonstrating that a similar complement of exocytotic proteins results in differing functional rate kinetics across different tissues. The cellular content of S-nitrosylated syntaxin 4 has been shown to peak acutely within 5 min of glucose stimulation in both human islets and MIN6 β-cells (Wiseman et al., 2011[134]). Mutation in the gene encoding cysteine-141-syntaxin 4 prevents S-nitrosylation induced by the NO donor (S-nitrosoglutathione), fails to exhibit glucose-induced activation and VAMP2 binding, and consequently fails to potentiate insulin release (Wiseman et al., 2011[134]). In addition, monitoring of single-cell exocytosis, using the styryl dye, FM1 43, demonstrates that NO (hydroxylamine, SNP, and SIN-1) exerts a rapid stimulatory effect on insulin secretion from INS-1 cells (Smukler et al., 2002[116]).","divisions":[{"label":"title","span":{"begin":0,"end":41}},{"label":"p","span":{"begin":42,"end":1410}},{"label":"p","span":{"begin":1411,"end":2452}}],"tracks":[{"project":"MyTest","denotations":[{"id":"33088259-12707306-29829844","span":{"begin":186,"end":189},"obj":"12707306"},{"id":"33088259-21393240-29829845","span":{"begin":213,"end":216},"obj":"21393240"},{"id":"33088259-24135953-29829846","span":{"begin":238,"end":240},"obj":"24135953"},{"id":"33088259-30053375-29829847","span":{"begin":266,"end":269},"obj":"30053375"},{"id":"33088259-12707306-29829848","span":{"begin":493,"end":496},"obj":"12707306"},{"id":"33088259-12707306-29829849","span":{"begin":766,"end":769},"obj":"12707306"},{"id":"33088259-30053375-29829850","span":{"begin":949,"end":952},"obj":"30053375"},{"id":"33088259-12707306-29829851","span":{"begin":1160,"end":1163},"obj":"12707306"},{"id":"33088259-8663999-29829852","span":{"begin":1683,"end":1685},"obj":"8663999"},{"id":"33088259-8663999-29829853","span":{"begin":2008,"end":2010},"obj":"8663999"},{"id":"33088259-8663999-29829854","span":{"begin":2103,"end":2105},"obj":"8663999"},{"id":"33088259-18452404-29829855","span":{"begin":2365,"end":2367},"obj":"18452404"},{"id":"33088259-21393240-29829856","span":{"begin":2644,"end":2647},"obj":"21393240"},{"id":"33088259-24135953-29829857","span":{"begin":2669,"end":2671},"obj":"24135953"},{"id":"33088259-17634254-29829858","span":{"begin":2790,"end":2793},"obj":"17634254"},{"id":"33088259-18452404-29829859","span":{"begin":2816,"end":2818},"obj":"18452404"},{"id":"33088259-21393240-29829860","span":{"begin":3203,"end":3206},"obj":"21393240"},{"id":"33088259-21393240-29829861","span":{"begin":3475,"end":3478},"obj":"21393240"},{"id":"33088259-12453899-29829862","span":{"begin":3710,"end":3713},"obj":"12453899"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"attributes":[{"subj":"33088259-12707306-29829844","pred":"source","obj":"MyTest"},{"subj":"33088259-21393240-29829845","pred":"source","obj":"MyTest"},{"subj":"33088259-24135953-29829846","pred":"source","obj":"MyTest"},{"subj":"33088259-30053375-29829847","pred":"source","obj":"MyTest"},{"subj":"33088259-12707306-29829848","pred":"source","obj":"MyTest"},{"subj":"33088259-12707306-29829849","pred":"source","obj":"MyTest"},{"subj":"33088259-30053375-29829850","pred":"source","obj":"MyTest"},{"subj":"33088259-12707306-29829851","pred":"source","obj":"MyTest"},{"subj":"33088259-8663999-29829852","pred":"source","obj":"MyTest"},{"subj":"33088259-8663999-29829853","pred":"source","obj":"MyTest"},{"subj":"33088259-8663999-29829854","pred":"source","obj":"MyTest"},{"subj":"33088259-18452404-29829855","pred":"source","obj":"MyTest"},{"subj":"33088259-21393240-29829856","pred":"source","obj":"MyTest"},{"subj":"33088259-24135953-29829857","pred":"source","obj":"MyTest"},{"subj":"33088259-17634254-29829858","pred":"source","obj":"MyTest"},{"subj":"33088259-18452404-29829859","pred":"source","obj":"MyTest"},{"subj":"33088259-21393240-29829860","pred":"source","obj":"MyTest"},{"subj":"33088259-21393240-29829861","pred":"source","obj":"MyTest"},{"subj":"33088259-12453899-29829862","pred":"source","obj":"MyTest"}]},{"project":"2_test","denotations":[{"id":"33088259-12707306-29829844","span":{"begin":186,"end":189},"obj":"12707306"},{"id":"33088259-21393240-29829845","span":{"begin":213,"end":216},"obj":"21393240"},{"id":"33088259-24135953-29829846","span":{"begin":238,"end":240},"obj":"24135953"},{"id":"33088259-30053375-29829847","span":{"begin":266,"end":269},"obj":"30053375"},{"id":"33088259-12707306-29829848","span":{"begin":493,"end":496},"obj":"12707306"},{"id":"33088259-12707306-29829849","span":{"begin":766,"end":769},"obj":"12707306"},{"id":"33088259-30053375-29829850","span":{"begin":949,"end":952},"obj":"30053375"},{"id":"33088259-12707306-29829851","span":{"begin":1160,"end":1163},"obj":"12707306"},{"id":"33088259-8663999-29829852","span":{"begin":1683,"end":1685},"obj":"8663999"},{"id":"33088259-8663999-29829853","span":{"begin":2008,"end":2010},"obj":"8663999"},{"id":"33088259-8663999-29829854","span":{"begin":2103,"end":2105},"obj":"8663999"},{"id":"33088259-18452404-29829855","span":{"begin":2365,"end":2367},"obj":"18452404"},{"id":"33088259-21393240-29829856","span":{"begin":2644,"end":2647},"obj":"21393240"},{"id":"33088259-24135953-29829857","span":{"begin":2669,"end":2671},"obj":"24135953"},{"id":"33088259-17634254-29829858","span":{"begin":2790,"end":2793},"obj":"17634254"},{"id":"33088259-18452404-29829859","span":{"begin":2816,"end":2818},"obj":"18452404"},{"id":"33088259-21393240-29829860","span":{"begin":3203,"end":3206},"obj":"21393240"},{"id":"33088259-21393240-29829861","span":{"begin":3475,"end":3478},"obj":"21393240"},{"id":"33088259-12453899-29829862","span":{"begin":3710,"end":3713},"obj":"12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