Titin-isoform dependence of titin-actin interaction and its regulation by S100A1/Ca2+ in skinned myocardium.
Titin, also known as connectin, is a large filamentous protein that greatly contributes to passive myocardial stiffness. In vitro evidence suggests that one of titin's spring elements, the PEVK, interacts with actin and that this adds a viscous component to passive stiffness. Differential splicing of titin gives rise to the stiff N2B and more compliant N2BA isoforms. Here we studied the titin-isoform dependence of titin-actin interaction and studied the bovine left atrium (BLA) that expresses mainly N2BA titin, and the bovine left ventricle (BLV) that expresses a mixture of both N2B and N2BA isoforms. For comparison we also studied mouse left ventricular (MLV) myocardium which expresses predominately N2B titin. Using the actin-severing protein gelsolin, we obtained evidence that titin-actin interaction contributes significantly to passive myocardial stiffness in all tissue types, but most in MLV, least in BLA, and an intermediate level in BLV. We also studied whether titin-actin interaction is regulated by S100A1/calcium and found that calcium alone or S100A1 alone did not alter passive stiffness, but that combined they significantly lowered stiffness. We propose that titin-actin interaction is a "viscous break" that is on during diastole and off during systole.
Fukushima
Hideto
H
Department of Physiology, Sarver Molecular Cardiovascular Research Program, University of Arizona, PO Box 245217, Tucson, AZ 85724, USA.
Chung
Charles S
CS
Granzier
Henk
H
D000199:Actins / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D064211:Connectin; D004548:Elasticity; D018260:Gelsolin / Q000494:pharmacology; D006325:Heart Atria / Q000737:chemistry / Q000378:metabolism; D006352:Heart Ventricles / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism*; D009129:Muscle Tonus / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms; D011494:Protein Kinases / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism*
D000199:Actins; D064211:Connectin; D018260:Gelsolin; D009124:Muscle Proteins; D020033:Protein Isoforms; D009418:S100 Proteins; C110294:S100A1 protein; D011494:Protein Kinases; D002118:Calcium