Physiological roles of junctional membrane complex formed by Ca^<2+> store and plasma membranes in excitation-contraction coupling of cardiac myocytes.

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In heart muscle cells, sarcoplasmic reticulum (SR) membranes function as the intracellular Ca^<2+> store. The SR membranes form a junctional membrane complex with cell surface membrane by juctophilins of SR proteins. In this study, we explored the functional roles of junctional membrane complex composed of SR and sarcolemmal membranes in the excitation-contraction coupling.Utilizing the junctophilin knockout mice, we thus conducted the following experiments. (1)An abnormal contractility induced by the knockout of juctophilins was obserbed and characterized in detail. The abnormal contractility was considered to be due to disorganized structures of junctional membrane complex. (2)The action potentials were measured from the mouse heart. The abnormal contractility by the knockout of juctophilins was ascribed to the alteration in the action potential configuration. (3)Myoplasmic Ca^<2+> was measured from the mouse heart. The abnormal contractility by the knockout of juctophilins was media … More ted by the influx of the extracellular Ca^<2+> into the myoplasm. (4)During the abnormal contraction by the knockout of juctophilins, Ca^<2+> waves moving around the myocytes were detected with the confocal laser microscopy. (5)L-type Ca^<2+> channel and ryanodine receptor are strucurally coupled with each other. The coupling ratio of the L-type Ca^<2+> channel and the ryanodine receptor, calculated from the whole-cell current data, was decreased by the knockout of juctophilins. (6)Many parameters of cardiovascular system were studied at the animal level. Wave forms of the electrocardiogram (ECG) were altered by the knockout of juctophilins.The cardiac SR membranes express not only juctophilins but also ryanodine receptors. The ryanodine receptors function as Ca^<2+>-induced Ca^<2+> release channels from the Ca^<2+> store in the SR membranes to trigger the heart muscle contraction. Therefore, we also conducted experiments mentioned above using the ryanodine receptor knockout mice. This ryanodine receptor knockout mice showed an abnormal contractility, which was, different from that of the junctophilin knockout animal.Taken together, the present data strongly suggest that the junctional membrane complex containing junctophilins and ryanodine receptors is essential to the excitation-contraction coupling. Intact expression of both junctophilins and ryanodine receptors in the SR membrane would be important for the normal heart contraction. Less