This article is part of a themed issue on GPCR. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
THEMED ISSUE: GPCR RESEARCH PAPER
The signal transduction cascade regulating the expression of the gap junction protein connexin43 by β-adrenoceptors
Article first published online: 25 AUG 2009
© 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Issue: GPCR
Volume 158, Issue 1, pages 198–208, September 2009
How to Cite
Salameh, A., Krautblatter, S., Karl, S., Blanke, K., Gomez, D. R., Dhein, S., Pfeiffer, D. and Janousek, J. (2009), The signal transduction cascade regulating the expression of the gap junction protein connexin43 by β-adrenoceptors. British Journal of Pharmacology, 158: 198–208. doi: 10.1111/j.1476-5381.2009.00344.x
- Issue published online: 25 AUG 2009
- Article first published online: 25 AUG 2009
- Received 23 February 2009; revised 25 March; accepted 1 April 2009
- congestive heart failure;
- hypertrophic cardiomyopathy;
- human cardiac biopsy
Background and purpose: In mammalian heart, connexin43 (Cx43) represents the predominant connexin in the working myocardium. As the β-adrenoceptor is involved in many cardiac diseases, we wanted to clarify the pathway by which β-adrenoceptor stimulation may control Cx43 expression.
Experimental approach: Cultured neonatal rat cardiomyocytes were stimulated with isoprenaline. Cx43 expression as well as activation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK, JUN NH2-terminal kinase (JNK) and nuclear translocation of the transcription factors activator protein 1 (AP1) and CRE-binding protein (CREB) were investigated. Additionally, we assessed Cx43 expression and distribution in left ventricular biopsies from patients without any significant heart disease, and from patients with either congestive heart failure [dilated cardiomyopathy (DCM)] or hypertrophic cardiomyopathy (HCM).
Key results: Isoprenaline exposure caused about twofold up-regulation of Cx43 protein with a pEC50 of 7.92 ± 0.11, which was inhibited by propranolol, SB203580 (4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)-1H-imidazole) (p38 inhibitor), PD98059 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) (MAPK 1 kinase inhibitor) (Alexis Biochemicals, San Diego, CA, USA) or cyclosporin A. Similar findings were obtained for Cx43 mRNA. Furthermore, Cx43 up-regulation was accompanied by phosphorylation of p38, p42/44 and JNK, and by translocation of AP1 and CREB to the nucleus. Analysis of Cx43 protein and mRNA in ventricular biopsies revealed that in patients with DCM, Cx43 content was significantly lower, and in patients with HCM, Cx43 content was significantly higher, relative to patients without any cardiomyopathy. More importantly, Cx43 distribution also changed with more Cx43 being localized at the lateral border of the cardiomyocytes.
Conclusion and implication: β-adrenoceptor stimulation up-regulated cardiac Cx43 expression via a protein kinase A and MAPK-regulated pathway, possibly involving AP1 and CREB. Cardiomyopathy altered Cx43 expression and distribution.