© 1995 American Heart Association, Inc.
Articles |
Myosin Light Chain–Actin Interaction Regulates Cardiac Contractility
From the Max-Delbrück-Center for Molecular Medicine (I.M.), Berlin; the Department for Physiology II (O.R.) and Department of Cardiac Surgery (A.B., T.T., C.F.V.), University of Heidelberg; and Abbott Laboratories (G.M.), European Research, Wiesbaden, Germany.
Correspondence to Dr I. Morano, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str 10, 13122 Berlin, Germany.
Abstract The amino-terminal domain of the essential myosin light chain (MLC-1) binds to the carboxy terminus of the actin molecule. We studied the functional role of this interaction by two approaches: first, incubation of intact and chemically skinned human heart fibers with synthetic peptide corresponding to the sequences 5 through 14 (P5-14), 5 through 8 (P5-8), and 5 through 10 (P5-10) of the human ventricular MLC-1 (VLC-1) to saturate actin-binding sites, and second, incubation of skinned human heart fibers with a monoclonal antibody (MabVLC-1) raised against the actin-interacting N-terminal domain of human VLC-1 using P5-14 as antigen to deteriorate VLC-1 binding to actin. P5-14 increased isometric tension generation of skinned human heart fibers at both submaximal and maximal Ca2+ activation, the maximal effective peptide dosage being in the nanomolar range. A scrambled peptide of P5-14 with random sequence had no effects up to 10-8 mol/L, ie, where P5-14 was maximally effective. P5-8 and P5-10 increased isometric force to the same extent as P5-14, but micromolar concentrations were required. Amplitude of isometric twitch contraction, rate of tension development, rate of relaxation, and shortening velocity at near-zero load of electrically driven intact human atrial fibers increased significantly on incubation with P5-14. These alterations were not associated with modulation of intracellular Ca2+ transients as monitored by fura 2 fluorescence measurements. Incubation of skinned human heart fibers with MabVLC-1 increased isometric tension at both submaximal and maximal Ca2+ activation levels, having a maximal effective concentration in the femtomolar range. We conclude that VLC-1–actin interaction modulates cardiac contractility and may be a target for new inotropic intervention.
Key Words: human heart • skinned fiber • myosin light chain • calcium transient • fura 2
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