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KMID : 0811720070110000090
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Korean Journal of Physiology & Pharmacology
2007 Volume.11 No. 0 p.90 ~ p.0
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Mechanism for Insensitivity of GIRK Current to Bradykinin in Mouse Atrial Myocytes
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Shan Yu-Cui
Ho Won-Kyung
Cho Ha-Na
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Abstract
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Modulation of G protein-gated inwardly rectifying K+ (GIRK) channels via G protein-coupled receptors is a prime mechanism regulating heart rate. We have shown in the previous study that regulation of cardiac GIRK channels by Gq protein coupled receptors (GqPCRs) is via phosphatidylinositol 4,5-bisphosphate (PIP2) depletion and it occurs in a receptor-specific manner. The inhibition of GIRK current (IGIRK) by phenylephrine(PE) was (mean±SE) 33.4±2.6%, but the extents of inhibition induced by bradykinin(BK) was negligible, only 9.0± 2.5%. Despite extensive studies, the molecular mechanism underlying receptor-specificity remains enigmatic. In the present study, we probed mechanism of receptor-specificity. We confirmed that BK could induce PIP2 hydrolysis in mouse atrial myocytes using a phospholipase C (PLC)δ pleckstrin homology domain-green fluorescent protein fusion constructs. One possibility of receptor specificity is that membrane PIP2 levels during stimulation of PLC by BK stimulation would be maintained high via a simultaneous activation of PIP2 resynthesis. To test this hypothesis, we blocked synthesis of PIP2 by 50μM wortmannin, phosphatidylinositol-4-kinase inhibitor. In the presence of wortmannin, BK-suppression of IGIRK was still 8.9 ± 2.3%, indistinguishable from BK effect in control condition. Furthermore, BK did not induce intracellular Ca2+ increases, which is supposed to be a mechanism of PIP2 synthesis during activation of bradykinin receptor. These results suggest that compensation for PIP2 hydrolysis does not contribute to receptor-specificity of Gq-mediated GIRK channel regulation. The results, taken in conjunction with previous data for GIRK channel regulation. By PIP2 (Cho et al., in press), And we found that after agonist treatment, α1- adrenergic receptor mostly fractionated to raft fraction, but BK B2 receptors mostly fractionated to non-raft fraction. This result indicates that BK receptor and α1- adrenergic receptor or GIRK channels create discrete signaling complexes. From the results above, we suggest the hypothesis that the differential regulation of IGIRK by different GqPCRs results from spatial proximity of receptor and channel protein.
Source: Korean Journal of Physiology & Pharmacology.2007 Oct;11(Suppl II):S83-S83
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KEYWORD
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GIRK, GqPCRs, BK, Wortmannin, Myocyte
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