G protein-coupled receptors (GPCRs) and their signaling pathways are the targets of many current therapeutics as well as drugs of abuse. Most currently used therapeutics were developed decades ago when few components of GPCR signaling systems were known. However, new therapeutics, such as agonists biased to evoke GPCR-arrestin signaling, are being developed as a consequence of identifying novel components and regulators of GPCR signaling networks. Such novel targets potentially enable long-standing problems associated with current therapeutics, such as drug tolerance, side effects or addiction, to be reduced or eliminated. This project addresses these long-term goals by identifying novel mechanisms that control GPCR signaling in the nervous system. It focuses on the R7 RGS family of G protein regulators, which have been shown genetically to be critical intracellular regulators of GPCR signaling throughout the nervous system, and which regulate the biological effects of opioids and amphetamines, and side effects of L-DOPA.
The Aims will determine how R7 RGS proteins under the control of a palmitoylated allosteric regulator called R7BP (R7 RGS-binding protein) regulate the activity of adenylyl cyclases and cAMP signaling in neuronal cells. They will identify novel enzymes that regulate palmitate turnover on R7BP and establish the functions of these enzymes as regulators of GPCR signaling in neuronal cells. Lastly, they will determine whether global or local cycles of palmitate turnover regulate the intracellular trafficking and function of R7BP-bound R7 RGS complexes. New knowledge gained by this project will provide deeper understanding of neurobiological signaling processes controlled by R7 RGS proteins, new models for elucidating the functions of palmitate turnover in diverse aspects of cell signaling and disease, and new drug targets that potentially enhance the action or reduce the side effects of GPCR-targeted neurotherapeutics.
Drug tolerance and side effects limit use of many therapeutic agents, including opioids in chronic pain and L- DOPA in Parkinson's disease. To improve clinical utility of therapeutics, investigators must identify molecular and cellular mechanisms tha regulate drug action to discover means of blunting or eliminating tolerance or dose-limiting side effects. These objectives will be addressed in this project by identifying molecular and cellular mechanisms that regulate the action of drugs that target G protein-coupled receptors in the nervous system. Enzymes controlling these mechanisms will be identified to establish them as new drug targets, potentially for enhancing opioid analgesia or reducing side effects of L-DOPA in Parkinson's disease.
|Jia, Lixia; Chisari, Mariangela; Maktabi, Mohammad H et al. (2014) A mechanism regulating G protein-coupled receptor signaling that requires cycles of protein palmitoylation and depalmitoylation. J Biol Chem 289:6249-57|
|Osei-Owusu, Patrick; Sabharwal, Rasna; Kaltenbronn, Kevin M et al. (2012) Regulator of G protein signaling 2 deficiency causes endothelial dysfunction and impaired endothelium-derived hyperpolarizing factor-mediated relaxation by dysregulating Gi/o signaling. J Biol Chem 287:12541-9|
|Jia, Lixia; Linder, Maurine E; Blumer, Kendall J (2011) Gi/o signaling and the palmitoyltransferase DHHC2 regulate palmitate cycling and shuttling of RGS7 family-binding protein. J Biol Chem 286:13695-703|
|Jayaraman, Muralidharan; Zhou, Hao; Jia, Lixia et al. (2009) R9AP and R7BP: traffic cops for the RGS7 family in phototransduction and neuronal GPCR signaling. Trends Pharmacol Sci 30:17-24|
|Gu, Steven; Anton, Annepa; Salim, Samina et al. (2008) Alternative translation initiation of human regulators of G-protein signaling-2 yields a set of functionally distinct proteins. Mol Pharmacol 73:1-11|
|Grabowska, D; Jayaraman, M; Kaltenbronn, K M et al. (2008) Postnatal induction and localization of R7BP, a membrane-anchoring protein for regulator of G protein signaling 7 family-Gbeta5 complexes in brain. Neuroscience 151:969-82|
|Blumer, Kendall J; Thorner, Jeremy (2007) An adrenaline (and gold?) rush for the GPCR community. ACS Chem Biol 2:783-6|
|Osei-Owusu, Patrick; Sun, Xiaoguang; Drenan, Ryan M et al. (2007) Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase. J Biol Chem 282:31656-65|
|Drenan, Ryan M; Doupnik, Craig A; Jayaraman, Muralidharan et al. (2006) R7BP augments the function of RGS7*Gbeta5 complexes by a plasma membrane-targeting mechanism. J Biol Chem 281:28222-31|
|Kim, Kyoungtae; Galletta, Brian J; Schmidt, Kevin O et al. (2006) Actin-based motility during endocytosis in budding yeast. Mol Biol Cell 17:1354-63|
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