Beta Adrenergic Receptor Signaling in Gravin Knockout Mice
| dc.contributor.advisor | McConnell, Bradley K. | |
| dc.contributor.committeeMember | Bond, Richard A. | |
| dc.contributor.committeeMember | Lokhandwala, Mustafa F. | |
| dc.contributor.committeeMember | Oyekan, Adebayo O. | |
| dc.contributor.committeeMember | Huang, Ming-He | |
| dc.creator | Guillory, Ashley | |
| dc.date.accessioned | 2018-03-14T17:22:56Z | |
| dc.date.available | 2018-03-14T17:22:56Z | |
| dc.date.created | December 2012 | |
| dc.date.issued | 2012-12 | |
| dc.date.submitted | December 2012 | |
| dc.date.updated | 2018-03-14T17:22:56Z | |
| dc.description.abstract | Beta-adrenergic receptors (beta-AR) signal through protein kinase A (PKA)-dependent phosphorylation, which affects calcium (Ca2+) homeostasis to increase contractility. PKA binds to A-kinase anchoring proteins (AKAPs) which localize PKA and its substrates to defined subcellular locations. Gravin, an AKAP, targets PKA, protein kinase C (PKC), and other signaling molecules to the beta2-AR. Gravin mediates desensitization/resensitization of the receptor by facilitating its phosphorylation by PKA and PKC. However, the role of gravin in beta-AR mediated regulation of cardiac function is unclear. We measured various aspects of the beta-AR signaling pathway in wild-type (WT) and gravin knockout (KO) mice after acute beta-AR stimulation by the nonspecific agonist isoproterenol (ISO). Using echocardiographic analysis, we observed that left ventricular fractional shortening and cardiac output were increased in KO animals compared to WT animals before and after ISO treatment. cAMP production, PKA activity and phosphorylation of phospholamban and troponin I was comparable in WT and KO hearts regardless of treatment. However, basal cardiac myosin binding protein C phosphorylation at position 273 was significantly increased in KO versus WT hearts. Additionally, heat shock protein 20 (Hsp20) was significantly more phosphorylated in KO versus WT hearts, following ISO treatment. We also measured the beta-AR signaling pathway following chronic ISO stimulation. Using echocardiography analysis, we observed that cardiac contractility remained significantly increased in KO mice after chronic ISO treatment compared to WT mice. Additionally, the absence of gravin blocked the ISO-induced desensitization of beta1-ARs seen in chronically stimulated WT hearts while beta2-AR density was significantly increased in ISO treated KO hearts. Furthermore, we observed alterations in PKA phosphorylation of phospholamban, troponin I, myosin binding protein C and protein phosphatase-1 inhibitor-1 that may have a positive effect on cardiac function. Our results demonstrate that gravin does play a substantial role in modulating beta-AR signaling by increasing baseline cardiac function as well as continuing to augment contractility in response to acute and chronic beta-AR stimulation. Furthermore, the absence of gravin appears to abrogate many of the maladaptive changes associated with chronic beta-AR stimulation. Thus, we propose that gravin may be a viable therapeutic target to modulate cardiac function in disease states. | |
| dc.description.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| dc.format.digitalOrigin | born digital | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/10657/2969 | |
| dc.language.iso | eng | |
| dc.rights | The author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s). | |
| dc.subject | Gravin | |
| dc.subject | Beta-adrenergic receptors | |
| dc.subject | Contractility | |
| dc.subject | Signal transduction | |
| dc.title | Beta Adrenergic Receptor Signaling in Gravin Knockout Mice | |
| dc.type.dcmi | Text | |
| dc.type.genre | Thesis | |
| thesis.degree.college | College of Pharmacy | |
| thesis.degree.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| thesis.degree.discipline | Cardiovascular Pharmacology | |
| thesis.degree.grantor | University of Houston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Pharmacology |