Evidence that the H1-H2 domain of α1 subunit of (Na + +K + )-ATPase participates in the regulation of cardiac contraction Kai Y. Xu 1 , Eiki Takimoto * , George J. Juang * , Qi Zhang, Holly Rohde † and Allen C. Myers † Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, USA; * Department of Medicine, Division of Cardiology, † Division of Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 1 Correspondence: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene St., Room 308, Baltimore, MD 21201, USA. E-mail: kxu002@umaryland.edu (Na + +K + )-ATPase (NKA) plays an important role in ion homeostasis and regulates cardiac contraction. To understand the molecular basis of its cardiac regulatory functions, we investigated whether the primary structure of the H1-H2 domain in α-1 (α1) subunit of the enzyme plays a role in myocardial contractile regulation. Here we show that site-specific binding to this α1 H1-H2 domain with a targeted antibody (SSA78) markedly augments intracellular Ca 2+ transients and contraction of rat ventricular cardiomyocytes without inactivating NKA. In vivo SSA78 infusion in mice results in a positive inotropic effect with enhanced contractile function yet no change in relaxation, indicating a direct cardiac effect linked to the H1-H2 domain. Competitive immunofluorescent staining and flow cytometry reveal that SSA78 binding is antagonized by ouabain, supporting the interaction of SSA78 at one of the glycoside-effecter sites. These new findings suggest that the H1-H2 domain of α1 subunit of NKA is a critical determinant of enzyme biologic activity, which couples to enhanced myocyte calcium transient and inotropic action.—Xu, K. Y., Takimoto, E., Juang, G. J., Zhang, Q., Rohde, H., Myers, H. C. Evidence that the H1-H2 domain of α1 subunit of (Na + +K + )-ATPase participates in the regulation of cardiac contraction. Key Words: structure and function • antibody • positive inotropic effect • molecular regulation
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Evidence that the H1-H2 domain of α1 subunit of (Na++K+)-ATPase participates in the regulation of cardiac contraction
Xu, Kai Y.; Takimoto, Eiki; Juang, George J.; Zhang, Qi; Rohde, Holly; Myers, Allen C.
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, Volume 19 (1): 53
Fed of American Socs for Experimental Biology – Jan 1, 2005
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