The focus of my research in recent years has been the intracellular signaling that occurs in response to cell surface receptor activation. In particular, I have studied inositol 1, 4, 5-trisphosphate (InsP3) receptors, proteins that form channels in endoplasmic reticulum (ER) membranes and which, in response to InsP3 binding, mobilize Ca2+ stored within the ER. My long-term objectives are (i) to understand the role of InsP3 receptors in intracellular signaling, (ii) to define mechanisms that regulate InsP3 receptors and other signaling proteins, and (iii) to establish the biological significance of InsP3 receptor regulation. Since 1991, I have studied InsP3 receptor down-regulation, a novel adaptive response to cell surface receptor activation that rapidly reduces cellular InsP3 receptor content and, thus, the sensitivity of ER Ca2+ stores to InsP3. Recently, it has been shown that InsP3 receptor down-regulation is mediated by the ubiquitin / proteasome pathway, a crucial pathway for the degradation of many cellular proteins that is currently being considered as a therapeutic target. Ubiquitination of InsP3 receptors is the event that initiates their degradation.
The Specific Aims of the current proposal are (1) to define the site(s) of ubiquitination in InsP3 receptors using biochemical techniques and InsP3 receptor mutagenesis, (2) to identify the enzymes responsible for InsP3 receptor ubiquitination using biochemical techniques and transfection of cDNAs encoding these enzymes, (3) to define the signaling events that accelerate InsP3 receptor ubiquitination using InsP3 receptor mutagenesis, and (4) to characterize InsP3 receptor ubiquitination and down-regulation in rat brain. Accomplishment of these Aims will define the events that cause InsP3 receptor ubiquitination and will provide information on it's biological significance. The health relevance of this work is threefold. First, it will lead to a better understanding of mechanisms that cells use to adapt to extracellular stimuli; such adaptation is the basis for many physiological modifications to cell function and of tolerance to the effects of many therapeutic and recreational drugs. Second, it will establish whether muscarinic agonists used in the treatment of Alzheimer's disease cause InsP3 receptor ubiquitination and down-regulation in vivo. Third, it will help to map the ubiquitin / proteasome pathway and, thus, will provide a better understanding of drugs designed to interfere with this process.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pharmacology A Study Section (PHRA)
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Haft, Carol R
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Upstate Medical University
Schools of Medicine
United States
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Schulman, Jacqualyn J; Wright, Forrest A; Han, Xiaobing et al. (2016) The Stability and Expression Level of Bok Are Governed by Binding to Inositol 1,4,5-Trisphosphate Receptors. J Biol Chem 291:11820-8
Wright, Forrest A; Lu, Justine P; Sliter, Danielle A et al. (2015) A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate Receptor-mediated Ca2+ Signaling. J Biol Chem 290:13948-57
Sathanawongs, Anucha; Fujiwara, Katsuyoshi; Kato, Tsubasa et al. (2015) The effect of M-phase stage-dependent kinase inhibitors on inositol 1,4,5-trisphosphate receptor 1 (IP3 R1) expression and localization in pig oocytes. Anim Sci J 86:138-47
Schulman, Jacqualyn J; Wright, Forrest A; Kaufmann, Thomas et al. (2013) The Bcl-2 protein family member Bok binds to the coupling domain of inositol 1,4,5-trisphosphate receptors and protects them from proteolytic cleavage. J Biol Chem 288:25340-9
Hirose, Masahiko; Kamoshita, Maki; Fujiwara, Katsuyoshi et al. (2013) Vitrification procedure decreases inositol 1,4,5-trisphophate receptor expression, resulting in low fertility of pig oocytes. Anim Sci J 84:693-701
Tsai, Yien Che; Leichner, Gil S; Pearce, Margaret M P et al. (2012) Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system. Mol Biol Cell 23:4484-94
Sliter, Danielle A; Aguiar, Mike; Gygi, Steven P et al. (2011) Activated inositol 1,4,5-trisphosphate receptors are modified by homogeneous Lys-48- and Lys-63-linked ubiquitin chains, but only Lys-48-linked chains are required for degradation. J Biol Chem 286:1074-82
Pednekar, Deepa; Wang, Yuan; Fedotova, Tatyana V et al. (2011) Clustered hydrophobic amino acids in amphipathic helices mediate erlin1/2 complex assembly. Biochem Biophys Res Commun 415:135-40
Lu, Justine P; Wang, Yuan; Sliter, Danielle A et al. (2011) RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase, mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation. J Biol Chem 286:24426-33
Pearce, Margaret M P; Wormer, Duncan B; Wilkens, Stephan et al. (2009) An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate receptors. J Biol Chem 284:10433-45

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