The long-term goal of this application is to elucidate neurochemical aspects of signal transduction systems in the brain which may be the site of action for psychotropic drug actions. Studies are proposed to clarify properties of the phosphoinositide and nitric oxide messenger systems. Properties of the inositol-1,4,5-triphosphate (IP3) receptor protein will be characterized. The biochemical and functional role of phosphorylation and glycosylation of the receptor will be examined. Functional role of phosphorylation and glycosylation of the receptor will be evaluated through a reconstituted system of the IP3 receptor protein in liposomes whereby calcium flux is stimulated selectively by IP3 Properties of IP3 receptor protein in peripheral tissues will be compared with the central receptor. The receptor protein for inositol (1,3,4,5) tetrakisphosphate (IP4) will be purified. Antisera will be developed to the IP4 receptor protein to permit its immunohistochemical localization. Utilizing the purified IP4 receptor protein reconstituted into liposomes, efforts will be made to identify potential functions ,such as mediation of ion flux. Calmedin, a membrane associated protein in the brain which mediates the ability of calcium to inhibit IP3 receptor binding, will be purified Interactions between purified calmedin and IP3 receptor protein will be examined in kinase, which generates IP4, will be purified. Antisera to the purified enzyme proteins will be employed for immunohistochemistry. Nitric oxide (NO) will be characterized as a possible messenger in neuronal interactions in the brain. The relationship between the conversion of arginine to citrulline and the formation of NO will be examined in a variety of systems. The nature of the endogenous arginine pool employed for NO biosynthesis will be explore by examining the uptake of 3H-arginine and alterations in endogenous arginine levels. The influence of agents that affect free radical formation will be examined on NO and cyclic GMP formation. The cellular source of NO synthesis will be explored utilizing neurologic mutant mice. The NO forming enzyme will be purified and antisera raised for immunohistochemical localization.
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| Kornberg, Michael D; Bhargava, Pavan; Kim, Paul M et al. (2018) Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360:449-453 |
| Sbodio, Juan I; Snyder, Solomon H; Paul, Bindu D (2018) Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington's disease. Proc Natl Acad Sci U S A 115:780-785 |
| Paul, Bindu D; Snyder, Solomon H (2018) Gasotransmitter hydrogen sulfide signaling in neuronal health and disease. Biochem Pharmacol 149:101-109 |
| Peng, Ying-Jie; Zhang, Xiuli; Gridina, Anna et al. (2017) Complementary roles of gasotransmitters CO and H2S in sleep apnea. Proc Natl Acad Sci U S A 114:1413-1418 |
| Sbodio, Juan I; Snyder, Solomon H; Paul, Bindu D (2016) Transcriptional control of amino acid homeostasis is disrupted in Huntington's disease. Proc Natl Acad Sci U S A 113:8843-8 |
| Kim, Hyo Jung; Cha, Jiyoung Y; Seok, Jo Woon et al. (2016) Dexras1 links glucocorticoids to insulin-like growth factor-1 signaling in adipogenesis. Sci Rep 6:28648 |
| Choi, Hyong Woo; Tian, Miaoying; Manohar, Murli et al. (2015) Human GAPDH Is a Target of Aspirin's Primary Metabolite Salicylic Acid and Its Derivatives. PLoS One 10:e0143447 |
| Paul, Bindu D; Snyder, Solomon H (2015) H2S: A Novel Gasotransmitter that Signals by Sulfhydration. Trends Biochem Sci 40:687-700 |
| Ahmed, Ishrat; Sbodio, Juan I; Harraz, Maged M et al. (2015) Huntington's disease: Neural dysfunction linked to inositol polyphosphate multikinase. Proc Natl Acad Sci U S A 112:9751-6 |
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