Control of Retinal Pericyte Excitability: Exploring the Role of Glucose, PGI2 and BKCa Channels

Hdl Handle:
http://hdl.handle.net/10675.2/344393
Title:
Control of Retinal Pericyte Excitability: Exploring the Role of Glucose, PGI2 and BKCa Channels
Authors:
Burnette, Jason O.
Abstract:
The retinal pericyte plays an important role in regulation of retinal capillary blood flow. Retinal pericytes express the large conductance, voltage and calcium-gated potassium channel (B K Ca), which exerts important control over membrane potential and excitability. To date, very little is known about the regulation of B K c a channel activity in retinal pericytes. Our findings indicate that high glucose (25mM) increases B K Ca channel activity and is consistent with previous studies demonstrating similar results. However, the cellular/molecular basis of this phenomenon is still undetermined. Our findings suggest that high glucose (25mM) induces expression of COX-2 in retinal pericytes, with subsequent production of P G I2. Furthermore, glucose may also exert its effects on pericyte excitability by altering the expression of B K c a channel subunits, thus influencing voltage and calcium gating of this ion channel. It has been shown that prostacyclin (PGI2 ) is the predominant prostanoid produced by the retinal pericyte, and this prostanoid can regulate pericyte contractility. However, the signaling pathway(s) governing this effect have yet to be elucidated. Our findings demonstrate that PGI2 increases B K c a channel activity. Furthermore, this activity can be reproduced using a cell permeable cyclic nucleotide, chlorophenylthio (CPT)-cAMP. We have further discovered that PGI2 as well as an increase in intracellular cAMP, regulates pericyte excitability by opening of BKCa channels via a process involving the cGMP-dependent protein kinase (PKG). Taken together, these findings suggest that high glucose can stimulate BKCa channel activity by inducing COX-2 expression and increasing PGI2 in the retinal pericyte, as well as by increasing BKCa 3-subunit expression. Furthermore we have demonstrated a novel signaling pathway for PGI2-stimulated BKCa channel activation: cAMP- dependent cross-activation of PKG.
Affiliation:
Department of Pharmacology and Toxicology
Issue Date:
Jun-2006
URI:
http://hdl.handle.net/10675.2/344393
Additional Links:
http://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/304957533?accountid=12365
Type:
Dissertation
Appears in Collections:
Department of Pharmacology and Toxicology Theses and Dissertations; Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorBurnette, Jason O.en
dc.date.accessioned2015-02-11T03:18:01Z-
dc.date.available2015-02-11T03:18:01Z-
dc.date.issued2006-06-
dc.identifier.urihttp://hdl.handle.net/10675.2/344393-
dc.description.abstractThe retinal pericyte plays an important role in regulation of retinal capillary blood flow. Retinal pericytes express the large conductance, voltage and calcium-gated potassium channel (B K Ca), which exerts important control over membrane potential and excitability. To date, very little is known about the regulation of B K c a channel activity in retinal pericytes. Our findings indicate that high glucose (25mM) increases B K Ca channel activity and is consistent with previous studies demonstrating similar results. However, the cellular/molecular basis of this phenomenon is still undetermined. Our findings suggest that high glucose (25mM) induces expression of COX-2 in retinal pericytes, with subsequent production of P G I2. Furthermore, glucose may also exert its effects on pericyte excitability by altering the expression of B K c a channel subunits, thus influencing voltage and calcium gating of this ion channel. It has been shown that prostacyclin (PGI2 ) is the predominant prostanoid produced by the retinal pericyte, and this prostanoid can regulate pericyte contractility. However, the signaling pathway(s) governing this effect have yet to be elucidated. Our findings demonstrate that PGI2 increases B K c a channel activity. Furthermore, this activity can be reproduced using a cell permeable cyclic nucleotide, chlorophenylthio (CPT)-cAMP. We have further discovered that PGI2 as well as an increase in intracellular cAMP, regulates pericyte excitability by opening of BKCa channels via a process involving the cGMP-dependent protein kinase (PKG). Taken together, these findings suggest that high glucose can stimulate BKCa channel activity by inducing COX-2 expression and increasing PGI2 in the retinal pericyte, as well as by increasing BKCa 3-subunit expression. Furthermore we have demonstrated a novel signaling pathway for PGI2-stimulated BKCa channel activation: cAMP- dependent cross-activation of PKG.en
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/304957533?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectRetinal Circulationen
dc.subjectPericyteen
dc.subjectDiabetesen
dc.subjectRetinaen
dc.subjectBKCa Channelsen
dc.subjectCOX-2en
dc.titleControl of Retinal Pericyte Excitability: Exploring the Role of Glucose, PGI2 and BKCa Channelsen
dc.typeDissertationen
dc.contributor.departmentDepartment of Pharmacology and Toxicologyen
dc.description.advisorWhite, Richard E.en
dc.description.committeeBarman, Scott; Caldwell, Ruth; Imig, John; Lambert, Nevinen
dc.description.degreeDoctor of Philosophy (Ph.D.)en
All Items in Scholarly Commons are protected by copyright, with all rights reserved, unless otherwise indicated.