Abstract:
: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).
journal_name
Exp Eye Resjournal_title
Experimental eye researchauthors
Burnette JO,White REdoi
10.1016/j.exer.2006.07.011subject
Has Abstractpub_date
2006-12-01 00:00:00pages
1359-65issue
6eissn
0014-4835issn
1096-0007pii
S0014-4835(06)00312-5journal_volume
83pub_type
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journal_title:Experimental eye research
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journal_title:Experimental eye research
pub_type: 杂志文章
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journal_title:Experimental eye research
pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Experimental eye research
pub_type: 杂志文章
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更新日期:2016-04-01 00:00:00
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journal_title:Experimental eye research
pub_type: 杂志文章,评审
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journal_title:Experimental eye research
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doi:
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journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2005.04.019
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pub_type: 杂志文章
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更新日期:2013-08-01 00:00:00
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journal_title:Experimental eye research
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abstract::Beta-crystallins are major protein constituents of the mammalian lens, where their stability and association into higher order complexes are critical for lens clarity and refraction. Dimerization is an initial step in formation of beta-crystallin complexes. Beta-crystallin association into dimers is energetically high...
journal_title:Experimental eye research
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