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Glucose Transporters and ATP-Gated K Metabolic Sensors Are + Glucose transporters and ATP-gated K (KATP) metabolic sensors are present in type 1 taste receptor 3 (T1r3)-expressing taste cells Karen K. Yeea,1, Sunil K. Sukumarana,1, Ramana Kothaa, Timothy A. Gilbertsonb, and Robert F. Margolskeea,2 aMonell Chemical Senses Center, Philadelphia, PA 19104-3308; and bDepartment of Biology, Center for Advanced Nutrition, Utah State University, Logan, UT 84322-5305 Edited* by Linda M. Bartoshuk, University of Florida, Gainesville, FL, and approved February 9, 2011 (received for review January 10, 2011) Although the heteromeric combination of type 1 taste receptors (11). In addition to Sac/Tas1r3, there are multiple quantitative 2 and 3 (T1r2 + T1r3) is well established as the major receptor for trait loci that contribute importantly to sweet taste responses in sugars and noncaloric sweeteners, there is also evidence of T1r- mice (3, 18). Physiological studies with canine lingual epithelium independent sweet taste in mice, particularly so for sugars. Before identified sugar-activated cation currents proposed to function as the molecular cloning of the T1rs, it had been proposed that sweet a sweet receptor (19–21). Plausible candidates to mediate T1r- taste detection depended on (a) activation of sugar-gated cation independent sweet taste include intestinal sugar transporters channels and/or (b) sugar binding to G protein-coupled receptors important in the absorption of dietary carbohydrate (reviewed in + to initiate second-messenger cascades. By either mechanism, sug- refs. 22 and 23) and the ATP-gated K (KATP) channel that serves ars would elicit depolarization of sweet-responsive taste cells, as a metabolic sensor in pancreatic islet cells (reviewed in refs. 24 which would transmit their signal to gustatory afferents. We and 25). Here, we used PCR, in situ hybridization, and immu- examined the nature of T1r-independent sweet taste; our start- nohistochemistry to determine if glucose transporters (GLUTs), ing point was to determine if taste cells express glucose transport- sodium–glucose cotransporters (SGLTs), and KATP subunits ers (GLUTs) and metabolic sensors that serve as sugar sensors in are expressed in taste cells. We also assessed electrophysiologi- other tissues. Using RT-PCR, quantitative PCR, in situ hybridization, cally if functional KATP channels were present in taste cells. Our and immunohistochemistry, we determined that several GLUTs results suggest that these signaling proteins may provide T1r- (GLUT2, GLUT4, GLUT8, and GLUT9), a sodium–glucose cotrans- independent sugar-sensing mechanisms in the sweet-responsive + porter (SGLT1), and two components of the ATP-gated K (KATP) subset of taste cells. metabolic sensor [sulfonylurea receptor (SUR) 1 and potassium in- wardly rectifying channel (Kir) 6.1] were expressed selectively in Results taste cells. Consistent with a role in sweet taste, GLUT4, SGLT1, GLUTs and Metabolic Sensors Are Expressed in Taste Cells. To de- and SUR1 were expressed preferentially in T1r3-positive taste cells. termine if GLUTs known to be present in intestine and/or other Electrophysiological recording determined that nearly 20% of the tissues, or metabolic sensors involved in glucose sensing in the total outward current of mouse fungiform taste cells was com- pancreas might also be present in taste cells, we first examined posed of KATP channels. Because the overwhelming majority of expression of their mRNAs in taste and nontaste (NT) tissues. T1r3-expressing taste cells also express SUR1, and vice versa, it is cDNAs were prepared from taste buds isolated from mouse cir- + likely that KATP channels constitute a major portion of K channels cumvallate (CV) papillae and from lingual epithelial cells devoid in the T1r3 subset of taste cells. Taste cell-expressed glucose sensors of taste cells (negative control); PCR assays were then performed and KATP may serve as mediators of the T1r-independent sweet using primer pairs specific for cDNAs corresponding to GLUT2, taste of sugars. GLUT4, GLUT8, GLUT9B, SGLT1, sulfonylurea receptor (SUR) 1, SUR2A, SUR2B, potassium inwardly rectifying channel gustation | sensory transduction (Kir) 6.1, Kir6.2, and the insulin receptor. By PCR, we observed a higher level of expression of GLUT8, GLUT9B, SGLT1, SUR1, ultiple lines of evidence argue for the heteromeric combi- SUR2A, Kir 6.1, and the insulin receptor in cDNA from taste Mnation of type 1 taste receptors 2 and 3 (T1r2 + T1r3) as tissue than from NT tissue (Fig. 1 A and B). PCR indicated that being the primary sweet taste receptor (reviewed in ref. 1). The mRNAs for GLUT2, GLUT4, SUR2B, and Kir6.2 were not Tas1r3 gene encoding T1r3 is allelic to Sac (2–7), the major ge- expressed in greater amounts in taste vs. NT tissue (Fig. 1 A and netic determinant of saccharin and sugar preference in inbred B). Quantitative evaluation by real-time PCR (qRT-PCR) dem- mice (8–10). KO mice deficient in either Tas1r2 or Tas1r3 display onstrated elevated expression in taste tissue cDNA of GLUT8, profound deficits in their responses to sweeteners (11, 12). Het- GLUT9, SGLT1, SUR1, Kir 6.1, and the insulin receptor (Fig. 1 C erologous expression of the human form of T1r2 + T1r3 generates and D). GLUT4 and SUR2 were not found by qRT-PCR to be receptor activity responsive to a broad array of sweet compounds, more highly expressed in taste tissue cDNA, however (Fig. 1 C including monosaccharide and disaccharide sugars (e.g., glucose, fructose, sucrose), sugar alcohols, small-molecule noncaloric sweeteners (e.g., saccharin, cyclamate, sucralose, aspartame, Author contributions: K.K.Y., S.K.S., R.K., T.A.G., and R.F.M. designed research; K.K.Y., neotame), and large-molecule noncaloric sweeteners (e.g., mon- S.K.S., R.K., and T.A.G. performed research; K.K.Y., S.K.S., T.A.G., and R.F.M. analyzed data; and K.K.Y., S.K.S., T.A.G., and R.F.M. wrote the paper. ellin, thaumatin, brazzein) (7, 13–17). Heterologous expression of Conflict of interest statement: R.F.M. has a personal financial interest in the form of stock the rodent form of T1r2 + T1r3 generates a similarly broad-acting ownership in the Redpoint Bio company and is an inventor on patents and patent appli- receptor but without activity toward the “human-specific sweet- cations that have been licensed to the Redpoint Bio company. No other authors eners” (cyclamate, aspartame, neotame, monellin, and thauma- have conflicts. tin) recognized as sweet by humans and old world primates but not *This Direct Submission article had a prearranged editor. by rodents. 1K.K.Y. and S.K.S. contributed equally to this work. Several studies indicate that there are T1r-independent mech- 2To whom correspondence should be addressed. E-mail: [email protected]. anisms for detecting sugars, however. For example, KO mice This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. NEUROSCIENCE lacking T1r3 still respond to multiple sugars, particularly glucose 1073/pnas.1100495108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1100495108 PNAS | March 29, 2011 | vol. 108 | no. 13 | 5431–5436 Downloaded by guest on September 30, 2021 Fig. 2. Expression of sugar transporter and KATP glucose sensor mRNAs in taste cells. In situ hybridization to taste bud-containing tissues from mouse CV and foliate taste papillae was carried out with digoxigenin-labeled RNA probes. Taste-cell hybridization to antisense probes indicated expression in CV and foliate taste cells of GLUT2 (A and C), GLUT4 (E and G), GLUT9 (I and Fig. 1. Expression of sugar transporter, KATP glucose sensor, and insulin K), SGLT1 (M and O), and SUR1 (Q and S). Hybridization to sense probe receptor mRNAs in taste tissue. (A) PCR amplification (35 cycles) of sugar controls (B, D, F, H, J, L, N, P, R, and T) in and around taste cells indicative of transporters (GLUT2, GLUT4, GLUT8, GLUT9b, and SGLT1), gustducin (taste nonspecific background was generally lower than with the corresponding RNA control), and GAPDH (tissue RNA control) from mouse cDNA prepared antisense probes. (Scale bars: 20 μm.) from CV taste tissue and NT lingual epithelial tissue devoid of taste buds. GAPDH is expressed in both cDNA samples, but gustducin is expressed only in the taste cDNA. GLUT8, GLUT9b, and SGLT1 are more highly expressed in available antibodies was done to examine expression in taste cells taste cDNA. cDNAs prepared from tissues known to express these genes fi of GLUTs and KATP glucose sensor subunits. Immunoreactivity to served as positive controls (CTRL) to con rm the ability of primers to amplify GLUT2, GLUT4, SGLT1, SUR1, and Kir 6.1 was observed in the correctly sized product. GUST, gustducin. (B) PCR amplification (35 cycles) mouse taste cells of CV, foliate, and fungiform papillae (Fig. 3). of KATP subunits (SUR1, SUR2A, SUR2B, Kir6.1, and Kir6.2) and insulin re- fl ceptor from mouse cDNA prepared from CV taste tissue and NT lingual Interestingly, much of the SUR1 immuno uorescence appeared epithelial tissue devoid of taste buds. SUR1, SUR2A, Kir6.1, and INSR are to be concentrated within the nucleus of taste cells (Fig. 3 J–L). more highly expressed in taste cDNA. cDNAs prepared from tissues known to The nuclear pattern of staining of SUR1 was confirmed with express these genes served as controls to confirm the ability of primers to DAPI staining (Fig. S2 A–F); higher magnification and triple amplify the correctly sized product. INSR, insulin receptor. (C and D) Taqman staining for SUR1, DAPI, and lamin B indicated that SUR1 was real-time PCR was used to quantitate expression of sugar transporters, KATP internal to the nuclear envelope (Fig. S2 G–M). All primary subunits, and insulin receptor in CV (black bars) taste tissue and NT (gray bars) lingual epithelial tissue devoid of taste buds. Elevated expression in antibodies were validated for their ability to detect appropriate taste cDNA was observed for GLUT8, GLUT9, SGLT1, SUR1, Kir6.1, and insulin immunoreactivity in tissues known to express the proteins of in- receptor.
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