PGI2 opens potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG.

PGI2 opens potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG. Research Abstract Details 

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PGI2 opens potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG. Abstract Text:

Jason O Burnette,Richard E White,

Pericytes exert an important influence on the control of retinal blood flow; however, little is known regarding the molecular basis of retinal pericyte excitability. The purpose of this study was to elucidate the signaling pathway of how prostacyclin (PGI2), an important endogenous regulator of retinal blood flow, stimulates potassium channel activity in retinal pericytes. Retinal pericytes were isolated from porcine eyeballs and plated on glass coverslips. Immunocytochemistry was performed to verify expression of the pericyte-specific ganglioside marker, 3G5 and smooth muscle alpha-actin. Activity of the large-conductance, voltage- and calcium-activated potassium (BKCa) channel was measured in retinal pericytes via single-channel patch-clamp, and channel identification was confirmed via biophysical and pharmacological characterization. PGI2 (10 microM) or beraprost (30 microM; more stable prostacyclin analog) dramatically stimulated the activity of BKCa channels isolated in cell-attached patches. These experiments strongly suggested that PGI2 stimulated BKCa channel activity via a diffusible second messenger. Similarly, chlorophenylthio (CPT)-cAMP (100 microM; membrane permeable cAMP derivative) induced a significant increase in BKCa channel activity; however, inhibition of the cAMP-dependent protein kinase (PKA) with 300 nM KT5720 could not reverse the stimulatory effect of either PGI2 or CPT-cAMP. In contrast, activation of BK(Ca) channels with either CPT-cAMP or PGI2 was abolished by 300 nM KT5823 (n=5, p<0.01), an inhibitor of the cGMP-dependent protein kinase (PKG). In addition, PGI2-stimulated channel activity was also attenuated by Rp-8-CPT-cGMPS, which inhibits PKG activity via a different mechanism. These findings demonstrate that prostacyclin, the most abundant prostanoid in the retinal circulation, is a potent stimulator of BKCa channel activity in retinal pericytes. Interestingly, this response appears to involve cAMP-stimulated cross-activation of PKG, and not PKA. Taken together, these findings could explain, at least in part, the cellular/molecular basis for PGI2-induced pericyte relaxation and augmentation of blood flow in the retina. Further, we propose PKG-dependent stimulation of BKCa channel activity as a new potential therapeutic target to combat decreased retinal blood flow seen in some disease states (e.g., diabetic retinopathy).

PGI2 opens potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG. Publishing Authors By Initials

JO Burnette,RE White,

For similar animals: chordata: vertebrates: mammals: artiodactyla: swine research abstracts see: animals: chordata: vertebrates: mammals: artiodactyla: swine research

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PGI2 opens potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Experimental eye research

VOLUME: 83

Page Numbers: 1359-65

Journal Abbreviation: Exp. Eye Res.

ISSN: 0014-4835

DAY: 7

MONTH: 09

YEAR: 2006

PGI2 opens potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 370707

PGI2 opens potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG. Keywords Mesh Terms:

KEYWORDS: Swine

MESH TERMS: physiology

Chemical & Substance for Abstract: PGI2 opens potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG. Information

Substance Name: Cyclic GMP-Dependent Protein Kinases

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for PGI2 opens potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG.

AFFILIATION: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA.

Country: England

AGENCY: United States NHLBI

GRANT: HL076146

ACRONYM: HL

MEDLINETA: Exp Eye Res

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