ankyrin-b coordinates the nak atpase, naca exchanger, and insp3 receptor in a cardiac t-tubulesr microdomainankyrin-b协调nak atp酶、naca换热器和insp3受体在心脏t-tubulesr microdomain.pdfVIP

Open access, freely available online PLoS BIOLOGY Ankyrin-B Coordinates the Na/K ATPase, Na/Ca Exchanger, and InsP3 Receptor in a Cardiac T-Tubule/SR Microdomain 1* 2 2* Peter J. Mohler , Jonathan Q. Davis , Vann Bennett 1 Department of Pathology, Vanderbilt University, Nashville, Tennessee, United States of America, 2 Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, North Carolina, United States of America We report identification of an ankyrin-B-based macromolecular complex of Na/K ATPase (alpha 1 and alpha 2 isoforms), Na/Ca exchanger 1, and InsP3 receptor that is localized in cardiomyocyte T-tubules in discrete microdomains distinct from classic dihydropyridine receptor/ryanodine receptor ‘‘dyads.’’ E1425G mutation of ankyrin-B, which causes human cardiac arrhythmia, also blocks binding of ankyrin-B to all three components of the complex. The ankyrin-B complex is markedly reduced in adult ankyrin-Bþ/ cardiomyocytes, which may explain elevated [Ca2þ]i transients in these cells. Thus, loss of the ankyrin-B complex provides a molecular basis for cardiac arrhythmia in humans and mice. T-tubule-associated ankyrin-B, Na/Ca exchanger, and Na/K ATPase are not present in skeletal muscle, where ankyrin-B is expressed at 10-fold lower levels than in heart. Ankyrin-B also is not abundantly expressed in smooth muscle. We propose that the ankyrin-B-based complex is a specialized adaptation of cardiomyocytes with a role for cytosolic Ca2þ modulation. Citation: Mohler PJ, Davis JQ, Bennett V (2005) Ank