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Differential effects of the formin inhibitor SMIFH2 on contractility and Ca 2+ handling in frog and mouse cardiomyocytes
Author(s) -
Sakata Koji,
Matsuyama Sho,
Kurebayashi Nagomi,
Hayamizu Kengo,
Murayama Takashi,
Nakamura Kunihide,
Kitamura Kazuo,
Morimoto Sachio,
Takeya Ryu
Publication year - 2021
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12873
Subject(s) - contractility , biology , ryanodine receptor , actin , ryanodine receptor 2 , formins , inotrope , contraction (grammar) , medicine , microbiology and biotechnology , endocrinology , actin cytoskeleton , intracellular , cytoskeleton , biochemistry , cell
Genetic mutations in actin regulators have been emerging as a cause of cardiomyopathy, although the functional link between actin dynamics and cardiac contraction remains largely unknown. To obtain insight into this issue, we examined the effects of pharmacological inhibition of formins, a major class of actin‐assembling proteins. The formin inhibitor SMIFH2 significantly enhanced the cardiac contractility of isolated frog hearts, thereby augmenting cardiac performance. SMIFH2 treatment had no significant effects on the Ca 2+ sensitivity of frog muscle fibers. Instead, it unexpectedly increased Ca 2+ concentrations of isolated frog cardiomyocytes, suggesting that the inotropic effect is due to enhanced Ca 2+ transients. In contrast to frog hearts, the contractility of mouse cardiomyocytes was attenuated by SMIFH2 treatment with decreasing Ca 2+ transients. Thus, SMIFH2 has opposing effects on the Ca 2+ transient and contractility between frog and mouse cardiomyocytes. We further found that SMIFH2 suppressed Ca 2+ ‐release via type 2 ryanodine receptor (RyR2); this inhibitory effect may explain the species differences, since RyR2 is critical for Ca 2+ transients in mouse myocardium but absent in frog myocardium. Although the mechanisms underlying the enhancement of Ca 2+ transients in frog cardiomyocytes remain unclear, SMIFH2 differentially affects the cardiac contraction of amphibian and mammalian by differentially modulating their Ca 2+ handling.