G-protein-coupled receptor 41 in cardiomyocytes: Effect of butyrate on intracellular Ca 2+ and sarcomere shortening.

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.
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