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Cardiovascular Research Advance Access [Accepted Manuscript] published online on August 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn210
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

SYNTAXIN-1A INHIBITION OF P-1075, CROMAKALIM AND DIAZOXIDE ACTIONS ON MOUSE CARDIAC ATP-SENSITIVE POTASSIUM CHANNEL

Betty Ng1, Youhou Kang1, Huanli Xie1, Hui Sun1 and Herbert Y. Gaisano§,1

1 Departments of Medicine and Physiology, University of Toronto, Toronto, Canada M5S 1A8

§ Corresponding author : Herbert Y. Gaisano. Address: Room 7310 Medical Sciences Building, University of Toronto, Toronto, Ontario, M5S 1A8, Canada, Phone: (416) 978-1526. Fax: (416) 978-8765. Email: Herbert.gaisano{at}utoronto.ca

Aims: Syntaxin (Syn)-1A binds sulfonylurea receptor (SUR) nucleotide binding folds of cardiac myocyte (SUR2A) and islet β-cells (SUR1) to inhibit KATP channels. We further reported that Syn-1A reduced the potency and efficacy of β-cell-specific KATP channel openers (KCOs). Here, we examined whether Syn-1A would influence nonspecific (diazoxide) and SUR2-specific KCOs (N-cyano-N’-(1,1-dimethylpropyl)-N’’-3-pyridylguanidine (P-1075) and cromakalim) on cardiac myocyte KATP channels activation.

Methods: Confocal microscopy and Western blotting verified the presence of both Syn-1A and Syn-1B expression on rodent cardiac ventricular myocytes. Inside-out patch-clamp electrophysiology was utilized to examine the effects of these syntaxins on KATP macroscopic currents activated by various KCOs from a stable cell line expressing Kir6.2/SUR2A and from C57BL/6 male mouse ventricular myocytes.

Results: Syn-1A inhibited the current amplitude activated by P-1075, cromakalim and diazoxide via its H3 but not Habc domain. Syn-1B exhibited similar inhibitory effects on P-1075 activation of KATP currents. In examining for direct effects of Syn-1A on the KCO binding to cardiac SUR2 receptors, we found that Syn-1A did not directly affect [3H]-P-1075 binding to rat cardiac membrane SUR2A at maximum binding capacity, but was able to mildly reduce the affinity of cold P-1075 and cromakalim to displace [3H]-P-1075 binding.

Conclusion: In summary, Syn-1A (and Syn-1B) could inhibit KATP currents activated by SUR2A-acting KCOs. Potential fluctuations in the levels of these syntaxins in the myocardium may affect the therapeutic effectiveness of cardiac KCOs.

Time for primary review: 20 Days


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