Abstract Body (Do not enter title and authors here): GPCR-based taste receptors are expressed in taste buds where they mediate
perception of bitter, umami, and sweet taste qualities. Bitterness is recognized by type II taste
GPCRs (TAS2R), while umami and sweetness are detected by type I taste GPCRs
(TAS1R). There are three TAS1Rs which heterodimerize to form umami
(TAS1R1/TAS1R3) and sweet (TAS1R2/TAS1R3) receptors. Recently, extra-oral taste
receptors were found in tissues such as the airways, brain, and pancreas where they
function as toxin (bitter) and nutrient (umami/sweet) sensors. Studies also show cardiac
TAS1R mRNA expression, including tas1r1 and tas1r3. However, whether sweet taste
receptor (STR) proteins are expressed in the heart is not yet known. Here, using
immunoblotting and immunofluorescence, we show that TAS1R2 and TAS1R3 are
expressed in human and mouse myocardia, localized to the plasma membrane. To
investigate cardiac STR function, we stimulated hiPSC-derived engineered heart tissue
(EHT) and adult mouse cardiomyocytes with aspartame, a STR agonist, resulting in
positive inotropy and accelerated Ca²⁺ handling. To assess the pathway by which STR
signaling alters excitation-contraction coupling, we acutely stimulated neonatal rat
ventricular myocytes (NRVMs) with aspartame-treated growth media. Subsequently, we
fractionated the membrane from the cytosol and evaluated proteomic changes by mass
spectrometry. This revealed membrane enrichment of Gqα, a G-protein implicated in
IP₃-mediated Ca²⁺ efflux from the sarcoplasmic reticulum. Further, localization of
kinases (CAMKIID, SPEG, PKC) was altered. We gauged phosphorylation changes
following aspartame treatment in unfractionated NRVMs. Interestingly, phospholemman
was dephosphorylated, which is implicated in modulating contractility via NKA inhibition,
indirectly affecting NCX activity. High sugar diets are associated with higher arrhythmia
susceptibility. To evaluate if this results from cardiac STR overstimulation, we prolonged
aspartame treatment of adult mouse cardiomyocytes, resulting in a higher frequency of
irregular Ca²⁺ transients. Using RNAseq and immunoblotting, we show expression of
type I and II taste GPCRs is altered in human heart failure. Specifically, TAS1R2 is
upregulated in heart failure. We show that TAS1R2 overexpression is associated with
functional changes in EHTs when exposed to aspartame. Together, these results
uncover a novel GPCR pathway altering cardiac physiology in response to extracellular
nutrient detection.