Annexin A4 N‐terminal peptide inhibits adenylyl cyclase 5 and limits β‐adrenoceptor‐mediated prolongation of cardiac action potential
| Autor: | Wilhelm Schmitz, Christina Hermes, Andre Klemme, Alexander Heinick, Manuel Domnik, Frank U. Müller, Xenia Husser, Florentina Pluteanu, Volker Gerke |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Calcium Channels L-Type Action Potentials Stimulation Biochemistry Cell Line Adenylyl cyclase Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Annexin Cyclic AMP Genetics Animals Humans Myocyte Myocytes Cardiac Cyclic adenosine monophosphate Annexin A4 Molecular Biology Muscle Cells HEK 293 cells Heart Cardiac action potential Transfection Receptors Adrenergic Cell biology HEK293 Cells 030104 developmental biology chemistry 030217 neurology & neurosurgery Adenylyl Cyclases Biotechnology |
| Zdroj: | The FASEB Journal. 34:10489-10504 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.201902094rr |
| Popis: | Adenylyl cyclases (AC) are essential for the normal and pathophysiological response of many cells. In cardiomyocytes, the predominant AC isoforms are AC5 and AC6. Specific AC5 inhibition was suggested as an option for the treatment of heart failure potentially advantageous over β-blockers. We previously reported an interaction between the calcium-binding protein annexin A4 (ANXA4) and AC5 in human embryonic kidney 293 (HEK293) cells and an inhibition of cyclic adenosine monophosphate (cAMP) production in cardiomyocytes. Here, we investigated whether ANXA4 is able to differentiate between AC5 and AC6. In transfected HEK293 cells, ANXA4 specifically co-immunoprecipitated with AC5 and not with AC6, via its N-terminal domain. Both ANXA4 and a peptide comprising the ANXA4 N-terminal sequence (A4N1-22 ) decreased the cAMP production in AC5 and not in AC6 expressing cells. In line with ACs inhibition, in myocytes from ANXA4-deficient mice, β-adrenoceptor (βAR) stimulation led to a higher increase of the L-type calcium current (ICaL ) and to an excessive action potential duration (APD) prolongation as compared to wild-type cardiomyocytes. This enhanced response was reversed in the presence of A4N1-22 peptide likely via specific AC5 inhibition. We conclude that via the N-terminal domain ANXA4 inhibits AC5 not AC6, and that A4N1-22 as a specific AC5 inhibitor could serve as a novel therapeutic tool for the treatment of AC5-linked diseases. |
| Databáze: | OpenAIRE |
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