Loss of Annexin A7 Leads to Alterations in Frequency-Induced Shortening of Isolated Murine Cardiomyocytes

Abstract

Annexin A7 has been proposed to function in the fusion of vesicles, acting as a Ca²⁺ channel and as Ca²⁺-activated GTPase, thus inducing Ca²⁺/GTP-dependent secretory events. To understand the function of annexin A7, we have performed targeted disruption of the Anxa7 gene in mice. Matings between heterozygous mice produced offspring showing a normal Mendelian pattern of inheritance, indicating that the loss of annexin A7 did not interfere with viability in utero. Mice lacking annexin A7 showed no obvious phenotype and were fertile. To assay for exocytosis, insulin secretion from isolated islets of Langerhans was examined. Ca²⁺-induced and cyclic AMP-mediated potentiation of insulin secretion was unchanged in the absence of annexin A7, suggesting that it is not directly implicated in vesicle fusion. Ca²⁺ regulation studied in isolated cardiomyocytes, showed that while cells from early embryos displayed intact Ca²⁺homeostasis and expressed all of the components required for excitation-contraction coupling, cardiomyocytes from adultAnxa7^−/− mice exhibited an altered cell shortening-frequency relationship when stimulated with high frequencies. This suggests a function for annexin A7 in electromechanical coupling, probably through Ca²⁺homoeostasis.

ACKNOWLEDGMENTS

We thank Stephan Selbert, Olaf Weiner, Regine Brokamp, and Jana Köhler for help during the initial phase of this project, Andrea Hufschmidt, Berthold Gassen, and Rolf Müller for skilled technical help, Volker Gerke, Mitsumori Kawaminami, Walther van Venrooij, and Carlotta Zamparelli for providing reagents, Walter Witke for the genomic library, and Michael Schleicher for discussion.

S.U. is a recipient of a Heisenberg fellowship. This work was supported by grants from the DFG and the Center for Molecular Medicine Cologne to A.A.N.