G‐protein‐coupled receptor 41 in cardiomyocytes: Effect of butyrate on intracellular Ca2+ and sarcomere shortening

Abstract G‐protein‐coupled receptor 41 (GPR41) is a Gα i ‐coupled receptor activated by short‐chain fatty acids (SCFAs). Here, we tested that GPR41 is also expressed in cardiomyocytes and exerts a direct negative inotropic effect when activated by SCFA butyrate. Primary cardiomyocytes were isolated from wild‐type (WT) and GPR41 knockout (GPR41 −/− ) adult mice and intracellular Ca 2+ concentration and cell shortening were measured using the IonOptix system. RNA localization (RNAScope), quantitative real‐time polymerase chain reaction (qRT‐PCR), immunofluorescence staining, and western blot were used to examine the expression of GPR41 in adult primary cardiomyocytes of WT and GPR41 −/− mice. The effect of butyrate on shortening and intracellular Ca 2+ transient via GPR41 was also tested in cardiomyocytes. We demonstrated for the first time the presence of GPR41s on cardiomyocytes. Butyrate dose‐dependently decreased cell shortening and the amplitude of intracellular Ca 2+ transients in cardiomyocytes from WT but not GPR41 −/− mice. In WT cardiomyocytes, butyrate decreased caffeine‐mediated amplitudes of intracellular Ca 2+ transients from the sarcoplasmic reticulum (SR). Moreover, the inhibitory effects of butyrate on cell shortening and intracellular Ca 2+ were pertussis toxin (PTX)‐sensitive. Finally, butyrate decreased the activity of sarcoendoplasmic reticulum Ca 2+ ‐ATPase (SERCA) and cellular 3′‐5′‐cyclic adenosine monophosphate (cAMP) content. In conclusion, GPR41 is expressed on cardiomyocytes. Butyrate, a known GPR41 agonist, reduces cardiomyocyte shortening and intracellular Ca 2+ transient via decreasing Ca 2+ content in the SR by inhibiting SERCA activity in a PTX‐dependent manner. These findings establish that GPR41 is directly activated by SCFAs to decrease contraction and intracellular Ca 2+ transient, highlighting the potential inhibitory role of GPR41 in cardiomyocytes.