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Mechanisms Underlying the Pathogenesis of Atrial Arrhythmias in RGS4-deficient MiceMighiu, Alexandra Sorana 19 March 2014 (has links)
Atrial arrhythmias are very common clinically relevant conditions that are strongly associated with aging and parasympathetic tone. Additionally, ATP-sensitive K+ (KATP) channel activation has been reported to facilitate the development of re-entrant atrial arrhythmias. Since KATP channels are direct effectors of Gαi/o and RGS4 is an inhibitor of Gαi/o-signaling, we here investigate whether KATP channel activity is increased under decreased RGS4 activity in a manner that enhances susceptibility to AF. We show that loss of RGS4 facilitates the induction of atrial arrhythmias under parasympathetic challenge both in whole animals and isolated atrial tissues. Furthermore, using both genetic disruption (Kir6.2 ablation) and pharmacologic blockade (tolbutamide), we show that loss of functional KATP channels decreases the incidence of pacing-induced re-entry and prolongs repolarization in RGS4-deficient atria. Our findings are consistent with the conclusion that enhanced KATP channel activity may contribute to pacing-induced re-entrant rotors in the RGS4-deficient mouse model.
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Mechanisms Underlying the Pathogenesis of Atrial Arrhythmias in RGS4-deficient MiceMighiu, Alexandra Sorana 19 March 2014 (has links)
Atrial arrhythmias are very common clinically relevant conditions that are strongly associated with aging and parasympathetic tone. Additionally, ATP-sensitive K+ (KATP) channel activation has been reported to facilitate the development of re-entrant atrial arrhythmias. Since KATP channels are direct effectors of Gαi/o and RGS4 is an inhibitor of Gαi/o-signaling, we here investigate whether KATP channel activity is increased under decreased RGS4 activity in a manner that enhances susceptibility to AF. We show that loss of RGS4 facilitates the induction of atrial arrhythmias under parasympathetic challenge both in whole animals and isolated atrial tissues. Furthermore, using both genetic disruption (Kir6.2 ablation) and pharmacologic blockade (tolbutamide), we show that loss of functional KATP channels decreases the incidence of pacing-induced re-entry and prolongs repolarization in RGS4-deficient atria. Our findings are consistent with the conclusion that enhanced KATP channel activity may contribute to pacing-induced re-entrant rotors in the RGS4-deficient mouse model.
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Identification of a novel anti-apoptotic protein and characterization of mammalian regulators of G protein signaling (RGSs) in yeastYang, Zhao, 1970- January 2007 (has links)
Regulators of G protein signaling (RGSs) are negative regulators of G protein coupled receptors (GPCRs). Our lab has demonstrated that yeast Saccharomyces cerevisiae is a useful system to study RGS and G protein signaling. Mammalian RGSs can be expressed in yeast and favored to interact with mammalian GPCRs as well. / Based on the observation that human RGS1 causes yeast cell growth arrest, I therefore used RGS1 expressing yeast cells to screen a mouse T cell cDNA library in order to find potential interacting proteins. From the screen, I identified a mouse sphingomyelin synthase 1 (SMS1) cDNA. By using a series of different apoptotic stimuli, such as hydrogen peroxide, osmotic stress, exogenous ceramide and its precursors, high temperature etc., SMS1 expression was found to suppress cell growth arrest and prevent viability decline, indicating that SMS1 represents an anti-apoptotic protein that functions by decreasing the intracellular level of pro-apoptotic ceramide. / Gene analysis further indicated that the SMS1 gene consists of 16 exons spread over a 256kb portion of mouse chromosome 19. It is alternatively spliced to produce 4 different transcripts (SMS1alpha1, SMS1alpha2, SMS1beta and SMS1gamma) and encode 3 different proteins (SMS1alpha, SMS1beta and SMS1gamma). Notably, I found that SMS1beta protein does not interfere with SMS1alpha anti-apoptotic function, although both of these two proteins contain the protein-protein interaction domain, sterile alpha motif (SAM), at their N-terminus. / I also carried out a study to examine GPCR-RGS interactions using the yeast expression system. Our lab had noticed that there was an extra RGS5 related protein that was detected by western blot analysis in the protein extracts prepared from yeast and HEK293 cells expressing RGS5. The size of the band was approximately 2 times the molecular weight of RGS5, indicating the possibility that RGS5 forms a dimer. To further examine this hypothesis, I, therefore, performed a series of experiments, included yeast 2 hybrid assays, to demonstrate that RGS5 does interact with itself. This is the first report that RGS can form a dimer. The implications for this finding are discussed in detail.
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Identification of a novel anti-apoptotic protein and characterization of mammalian regulators of G protein signaling (RGSs) in yeastYang, Zhao, 1970- January 2007 (has links)
No description available.
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Interaction of the G Beta Sub Five-RGS7 Complex with the Muscarinic Acetylcholine M3 ReceptorSandiford, Simone Laura 18 November 2009 (has links)
Regulators of G protein signaling (RGS) are a diverse group of proteins, which play a fundamental role in modulation of G protein coupled receptor signal transduction. RGS proteins are primarily known as GTPase activating proteins (GAPs) for Gá subunits. In addition to the RGS domain, which is responsible for GAP activity, most RGS proteins also contain other structural motifs. The R7 family of RGS proteins for example, which consists of RGS-6, 7, 9 and 11 gene products, also contains DEP, DHEX and GGL domains. All R7 RGS proteins are obligatory binding partners with G protein beta subunit, G beta sub five, which binds to the GGL domain. In my dissertation work, I provide insights into significance of the multi-domain architecture of G beta sub five-RGS7. I have identified a novel intramolecular interaction within the G beta sub five-RGS7 complex; between the DEP domain of RGS7 and G beta sub five subunit. My experimental evidence supports the idea that G beta sub five-RGS7 can exist in at least two hypothetical conformations: "closed" where the DEP domain and G beta sub five subunit are bound to each other, and "open" where DEP and G beta sub five are not interacting, and as a result both these proteins can associate with other binding partners. My results indicate that in its "open" conformation, G beta sub five-RGS7 can selectively inhibit calcium mobilization elicited by stimulated muscarinic acetylcholine receptor type 3 (M3R). This inhibition is mediated by direct interaction between the third intracellular loop of M3R and the DEP domain of RGS7. In addition to the effect on M3R signaling, I observed that the G beta sub five-RGS7 complex redistributes from the cytosol to endocytic vesicles in an M3R-specific manner. These results identify a novel molecular mechanism that can impart receptor-subtype selectivity on signal transduction via G protein-coupled receptors. Lastly, I have identified a small group of compounds that inhibits the DEP-G beta sub five interaction. These compounds may serve as starting points for design of G beta sub five-RGS7 modulators in the future.
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Differential coupling of RGS3s and RGS4 to GPCR-GIRK channel signaling complexes /Jaén, Cristina. January 2006 (has links)
Dissertation (Ph.D.)--University of South Florida, 2006. / Includes vita. Includes bibliographical references (leaves 110-125). Also available online via the World Wide Web.
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RGS proteins in experimental Parkinsonism and L-DOPA-induced dyskinesiaKo, Daniel January 2012 (has links)
Parkinson’s disease (PD) is a progressive neurodegenerative disorder producing a clinical syndrome of bradykinesia, rigidity and resting tremor. These motor symptoms appear due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and loss of dopamine in the striatum, which subsequently leads to an imbalance of the basal ganglia motor circuit. The most effective pharmacological treatment for PD is L-3,4-dihydroxyphenylalanine (L-DOPA), the immediate metabolic precursor of dopamine, which effectively restores motor function. L-DOPA is catabolised into dopamine and replaces neurotransmitter loss in PD. However, long-term L-DOPA treatment leads to abnormal involuntary movements (AIMs), such as L-DOPA-induced dyskinesia (LID), which reduces the quality of life in PD patients. Currently, there are no reliable pharmacological treatments for these motor complications. Clinical and preclinical studies have shown that development and expression of LID is linked to unregulated dopamine release and plasticity-induced changes of striatal dopaminergic and non-dopaminergic signalling pathways. The activities of these pathways can be modulated by neurotransmitter receptors of a specific classification, the G-protein-coupled receptor (GPCR) family. In turn, GPCRs are regulated by certain endogenous proteins, the regulators of G-protein signalling (RGS) proteins. Numerous RGS protein subtypes are expressed in the striatum but their roles in PD and LID remain poorly understood. Given the modulatory function of RGS proteins in the striatum, these endogenous factors may have pathophysiological roles in the expression of motor symptoms in PD and LID. The studies presented in this thesis investigated the roles of RGS proteins in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD and LID. Rats received unilateral 6-OHDA lesions of the right medial forebrain bundle to induce severe dopamine denervation. L-DOPA/benserazide (6/15 mg/kg) was then administered once daily for at least 21 days to induce stable abnormal involuntary movements (AIMs). In Chapter 2 of this thesis, increased levels of RGS2 and RGS4 mRNA were found in the rostral striatum of the unilateral 6-OHDA-lesioned rat model of LID. Moreover, elevated levels of RGS4 mRNA were specific to sensorimotor regions and positively correlated with AIMs severity. These molecular and behavioural data suggest that RGS4 proteins are involved in the expression of LID. In Chapters 3 and 4, behavioural studies conducted in the unilateral 6-OHDA-lesioned rat model of LID showed that acute inhibition of striatal RGS4 proteins reduced the expression of AIMs and improved overall motor function. Moreover, repeated de novo treatment with RGS4 protein inhibitors, in combination with L-DOPA, attenuated the development of AIMs and reduced the overexpression of preproenkephalin-B, a molecular marker of LID. These behavioural and molecular data suggest that blockade of RGS4 proteins can reduce the induction of LID. In Chapter 5, in vivo microdialysis conducted in the unilateral 6-OHDA-lesioned rat model of LID showed that systemic administration of RGS4 protein inhibitors, in combination with L-DOPA, attenuated unregulated striatal dopamine efflux. These data suggest that RGS4 proteins may regulate specific G-protein coupled receptors, such as 5-HT1A receptors, that modulate striatal dopamine release. In conclusion, the work presented in this thesis shows that RGS4 proteins play a pathophysiological role in the expression and development of LID. These proteins could mediate regulation of key neurotransmitter receptors involved in LID, making them a potential therapeutic target for the development of future treatments.
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