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Influence of membrane heterogeneity on G-protein coupled receptor signaling

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dc.contributor.advisor Scarlata, Suzanne en_US
dc.contributor.author Calizo, Rhodora Cristina Segui en_US
dc.contributor.other Department of Biochemistry and Structural Biology. en_US
dc.date.accessioned 2017-09-20T16:51:31Z
dc.date.available 2017-09-20T16:51:31Z
dc.date.issued 2013-12-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/76953 en_US
dc.description 169 pg. en_US
dc.description.abstract A highly crowded and heterogenous environment is the emerging picture of the plasma membrane that would explain the efficiency and fidelity of many signal transduction processes. We determined the effect of plasma membrane heterogeneity on the function and diffusion of components from two class A G protein coupled receptor (GPCR) pathways, the bradykinin type 2 (B2R)/Gα q and the mu-opioid receptor (µOR)/Gα i pathways, as well as the epidermal growth factor receptor. In the first part of this dissertation, we describe the effect of nanoscale plasma membrane heterogeneity, as exemplified by caveolae domains, on the B2R and µOR pathways. We find that caveolae domains increase the signaling potential of the B2R/Gα q pathway but not the µOR/Gα i pathway. FRET studies suggest that components of the B2R/Gα q pathway reside closer to caveolae domains compared to those of the µOR/Gα i pathway and this proximity mediated by molecular interactions of Gα q with Cav1. Diffusion measurements of these membrane proteins by Fluorescence Correlation Spectroscopy (FCS) and Fluorescence Recovery After Photobleaching (FRAP) show a discrepancy in the apparent diffusion coefficients obtained from the two methods which may be due to the geometry of caveolae domains. By FCS, an increased apparent diffusion was found for both B2R and Gα q in the presence of caveolae which may be due to the confined, anomalous diffusion of the membrane proteins due to Cav1 interactions. These studies make the prediction that Gα q-coupled receptors localize close to caveolae domains and their signaling properties impacted by the presence of caveolae domains, as compared to Gα i coupled receptors. In the second part of this dissertation, we describe studies on the effect of cell shape on the distribution of the EGFR and B2R. By numerical simulation with experimental validation with fluorescence imaging, we find that cell shape can influence the balance of reaction-diffusion processes of activated membrane receptors, causing a spatial gradient of receptors on the plasma membrane. Studies of membrane heterogeneity on the B2R/Gα q and EGFR pathways may have implications on the mechanotransduction and mechanosensing of many cells including cardiac, vascular and smooth muscle cells. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Biochemistry en_US
dc.subject.other FCS, FRET, GPCRs, membrane domains en_US
dc.title Influence of membrane heterogeneity on G-protein coupled receptor signaling en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Brown, Deborah en_US
dc.contributor.committeemember London, Erwin en_US
dc.contributor.committeemember Bowen, Mark en_US
dc.contributor.committeemember Neves, Susana. en_US

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