BPS2026 – The sweet taste receptor regulates cardiomyocyte bioenergetics

GPCR-based taste receptors are expressed in taste buds where they mediate perception of bitter, umami, and sweet qualities. Sweetness is detected by a heterodimer of type I GPCRs (TAS1R2/TAS1R3). Recently, extra-oral sweet taste receptors (STRs) were found in tissues, such as the airways, brain, and pancreas, where they are proposed to function as nutrient sensors. Studies also show cardiac TAS1R mRNA expression, including TAS1R1 and TAS1R3. We show that both TAS1R2 and TAS1R3, comprising the sweet taste receptor (STR), are expressed in human and mouse myocardia, localized to the plasma membrane. We demonstrate in adult mouse cardiomyocytes and iPSC-derived engineered heart tissue that STR stimulation with aspartame rapidly regulates excitation-contraction coupling. To investigate how STR signaling influences cellular signaling, we activated neonatal rat ventricular cardiomyocyte STRs and evaluated proteomic changes, both subcellularly and at the whole-cell level, by mass spectrometry. Our data revealed localization changes to kinases such as CAMKIID, SPEG, and PKC. Correspondingly, we investigated phosphorylation changes upon STR stimulation, revealing signaling consequences such as phospholemman dephosphorylation. Moreover, we show mitochondrial proteome alterations, including the loss of membrane-enriched electron transport chain components as well as regulators of mitochondrial fission and fusion. One significantly membrane-enriched protein was MAP1LC3A. This protein canonically accumulates on membranes to facilitate autophagy and mitophagy activation. To elucidate the effect of STR signaling on mitochondrial health, we performed live-cell imaging using both mitochondrial and lysosomal dyes, demonstrating that their channel overlap increases upon STR activation, suggesting a possible link between nutrient sensation and cardiomyocyte bioenergetic regulation. Together, these results begin to uncover a novel GPCR pathway altering cardiac physiology and energetics in response to extracellular nutrient detection.