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Metabotropic glutamate type 1 in tissue1–3

Ana San Gabriel, Takami Maekawa, Hisayuki Uneyama, and Kunio Torii

ABSTRACT taste. T1R1 and T1R3 in rodents are co-expressed at the anterior L-Glutamate confers cognitive discrimination for taste (de- (17) and respond to L-glutamate in vitro. However, it is not Downloaded from https://academic.oup.com/ajcn/article/90/3/743S/4597174 by guest on 27 2021 licious or savory) and dietary information to the brain through the an L-glutamate–specific receptor in rodents, and knocking out activation of G protein–coupled receptors in specialized taste re- T1R3 does not completely block the preference for umami or 2+ ceptor cells of the tongue. The taste heterologous receptor T1R1 L-glutamate stimuli in gustatory nerves (18). Ca -induced re- plus T1R3 is not sufficient to detect umami taste in mice. The lack sponses in null T1R3 mice showed smaller amplitudes with of T1R3 diminished but did not abolish nerve and behavioral re- L-glutamate in intact slice preparations than in wild tissue, al- sponses in null mice that still contained umami-sensitive taste re- though the number of sensitive cells was not noticeably altered ceptor cells. The remnant umami responses in T1R3 knockout mice (19). Moreover, responses to umami in mice are greater in the indicate that there are also T1R3 independent receptors. Metabo- glossopharyngeal nerve at the posterior tongue than in the chorda tropic 1 (mGluR1), which is widely expressed tympani that innervate the anterior tongue (20). The function of throughout the central and regulates synaptic sig- the G proteins a- and a- also depends on their naling, is another L-glutamate receptor candidate. It is found within distribution. These G proteins only mediate umami responses in taste buds, although the amount of L-glutamate in the perisynaptic taste buds from the anterior tongue (21). In the back of the tongue, l region is in the order of mol/L, whereas free dietary L-glutamate is T1R3 is mostly co-expressed with T1R2 to form the heterologous in the mmol/L range. We reexamined the expression of one mGluR1 sweet receptor (22). Together, GPCRs in addition to T1R1 plus variant with a lower affinity for L-glutamate that is found in fungi- T1R3 and G proteins other than a-gustducin and a-transducin form and circumvallate papillae. This taste mGluR1 receptor re- seem to regulate L-glutamate taste in the posterior tongue. sponds in vitro to the concentration of L-glutamate usually found It is known by Fos immunohistochemistry, a marker of neu- in foodstuffs. Am J Clin Nutr 2009;90(suppl):743S–6S. ronal activation, that projections of afferents from the anterior tongue to the nucleus of the solitary tract (NST) are topographically different from those of the glossopharyngeal INTRODUCTION nerve at the posterior tongue (23). At the same time, the pro- The discovery of multiple umami receptors in the past decade jections of the NST deliver information to local reflex pathways has helped to support the status of umami as a primary taste or the parabrachial nucleus, so these different regions from the quality that is different from sweet, bitter, sour, and salty (1, 2). chorda tympani or the glossopharyngeal nerve may support rich in naturally occurring free L-glutamate, the prototype different neuronal functions. Studies suggest that NST molecule for umami taste, are highly palatable (3, 4). This may that respond to the posterior tongue are more closely related to be because L-glutamate is a biologically active molecule (5), the local reflex circuits (24), but the number of umami taste inputs most abundant in milk (6), and a major source of from the anterior tongue that are processed in comparison with energy for the intestine (5). Inosine 5#-monophosphate (IMP) the posterior tongue is unknown. We cannot identify the specific and guanosine-5’-monophosphate (GMP) also have a weak sa- role of each putative umami receptor in the tongue from its vory effect. Both enhance the intensity of L-glutamate (4, 7)— regional distribution. a characteristic of umami taste. In the mouth, umami taste not Although there are studies that involve mGluR4 as a only confers cognitive discrimination but also induces physio- L-glutamate receptor in the posterior tongue, this article will logic responses, such as vagal efferent activation (9) and salivary only examine the structure of an mGluR1 variant located in flow responses of cephalic origin in preparation for digestion a subset of TRCs from circumvallate and foliate papillae of the and assimilation (9). posterior tongue and its function in vitro (12, 25). Umami substances act by binding G protein–coupled receptors (GPCRs) in specialized taste receptor cells (TRCs). In response, 1 From the Institute of Life Sciences, Ajinomoto Co, Inc, Kawasaki, TRCs generate action potentials that are transmitted to gustatory . 2 afferentfibersviaATPsignaling(10,11).Heterologousexpression, Presented at the "100th Anniversary Symposium of Umami Discovery: afferent nerve recordings, and behavioral studies have helped to The Roles of Glutamate in Taste, Gastrointestinal Function, Metabolism, and Physiology," held in Tokyo, Japan, September 10–13, 2008. postulate several GPCRs as umami receptors: metabotropic glu- 3 Address correspondence to K Torii, Institute of Life Sciences Ajinomoto tamate receptor 4 (mGluR4) (12), heterodimer T1R1 plus T1R3 Co, Inc, Suzuki-cho 1-1, Kawasaki-ku Kawasaki 210-8681, Japan. E-mail: (13, 14), and mGluR1 (15, 16). Initially, the T1R1 plus T1R3 [email protected]. heterodimer was considered the only receptor to subtend umami First published online July 1, 2009; doi: 10.3945/ajcn.2009.27462I.

Am J Clin Nutr 2009;90(suppl):743S–6S. Printed in USA. Ó 2009 American Society for Nutrition 743S 744S SAN GABRIEL ET AL DOES mGluR1 PLAY A ROLE IN TASTE ? sequence. We suggested that a (GTG) codon within the same The GPCR mGluR1 is an excitatory receptor mainly known to frame may be the initiation site. Although GTG is not a frequent be expressed in the postsynaptic somatodendritic region (26). In sequence of initiation, it is possible that GTG can function as the , it mediates the action of the neu- a tentative start codon. Blast analysis (NCBI) showed in mice rotransmitter L-glutamate. Neural development, synaptic plas- that, instead of GTG, ATG is in the same location that could ticity, neurodegeneration, and induction are some of function as a putative first methionine, whereas the human has the roles that mGluR1 play in the brain (27). Its main trans- a GTG like the rat. duction pathway relies on the G protein Gq and phospholipase A forward primer homologous to this particular region combined with reverse primers from the downstream sequence of C (PLC), which elevates inositol 1,4,5-triphosphate (IP3), with 2+ mGluR1 yielded a product of ’400 base pairs. In comparison the subsequent release of Ca from IP3-dependent intracellular Ca2+ stores. Other transduction cascades have also been shown with the intact NTD fragment from brain tissue, taste mGluR1 to be associated with mGluR1, including adenylate cyclase, lost ’950 base pairs with the truncation at the 5# end. As shown see in the illustration (Figure 1), truncated mGluR1 lacks most of tyrosine kinase, and map kinase ( reference 27 for a review). Downloaded from https://academic.oup.com/ajcn/article/90/3/743S/4597174 by guest on 27 September 2021 This broad signaling competence grants mGluR1 a diverse phys- the VF module (white box), where L-glutamate is supposed to iologic capacity. TRCs express the PLC b2 isoform (PLCb2), bind. Without the known L-glutamate binding site, it was nec- signaling components, and adenylyl cyclases (28–31). essary to confirm the activity of the taste truncated-mGluR1 in Thus, taste tissue seems to contain the machinery to support vitro. Brain and taste variant mGluR1 clones were generated mGluR1 function. However, mGluR1 is activated with lmol by reverse transcriptase polymerase chain reaction (RT-PCR) L-glutamate/L, whereas the amount of free L-glutamate from the (Figure 2D), from which we produced capped cRNA for their Xenopus diet is in the order of mmol L-glutamate/L, which is within the expression into oocytes. The efficiency of the in vitro saturation range of the receptor (26). expression system was lower for truncated mGluR1 than for mGluR1 is part of the Family C GPCRs. It has a 7 trans- brain mGluR1, but eggs with the truncated form that responded membrane (TM) motif responsible for G protein activation and to a high concentration of L-glutamate (1 mmol/L) showed a large extracellular N-terminal domain (NTD) where the ligand- a typical trace with low current amplitude (Figure 2C). Con- binding site resides (32, 33). The Venus flytrap (VF) module of centrations of L-glutamate ,1 mmol/L did not induce any cur- the NTD is structurally similar to the bacterial periplasmic rent in injected oocytes with the taste-mGluR1, only in the brain proteins (34), and it binds to amino acids, cations, and even type mGluR1 (Figure 2B). Because of the potential osmolarity + some peptides (35). Most chemosensory receptors that distin- effect of high L-glutamate u and Na on eggs submerged in test guish a diverse range of chemical cues belong to this family buffer, we did not test concentrations .30 mmol/L, but it is together with mGluRs: GABA B receptor, calcium-sensing likely that the receptor does not reach saturation with 30 mmol receptor, taste receptor T1rs, and the amino acid receptor L-glutamate/L. Eggs injected with water did not respond to 30 GPRC6A. This could explain the presence of mGluR1 in taste mmol glutamate/L (Figure 2A). At this moment, there is no tissue and its potential to participate in L-glutamate perception. proof to corroborate the protein size of mGluR1 in taste tissue. The crystal structure of mGluR1 indicates that its ligand-binding However, we have recent evidence of mGluR1expression in the domain involves the VF module within the NTD (36), and its stomach, and Western blot analysis showed a considerably activation depends on the disulfide-linked homodimer confor- shorter mGluR1 band than the generic mGluR1 from the brain mation (37). When receptors lose part of this VF module, the (41). Consequently, it seems that some tissues express shorter TM domain can function as a -like GPCR (38). Some mGluR1 transcripts than the ones typically found in the brain. mGluR1 noncompetitive antagonists do not need the large NTD We speculate that these shorter variants may accommodate to exert their action because they interact directly with the TM the necessity to detect larger concentrations of L-glutamate region (39). The reactivity of the TM domain in mGluR1 pro- poses a possible physiologic relevance for short variants without the entire VF module. Our group was the first to propose a specific structure for mGluR1 in taste papillae, the confor- mation of which has not yet been elucidated.

TRUNCATED mGluR1: STRUCTURE AND FUNCTION In a previous study, we identified a short taste-mGluR1 transcript using rapid amplification of 5# ends from isolated rat circumvallate and foliate papillae (15). The sequence of the 5# end coincided with the 3# end of the proceeding intron to exon 6. The first 170 nucleotides from the amplified sequence of taste mGluR1 corresponded to the very end of the last intron se- quence. There was a stop codon in-frame with the long open reading frame, which suggested that there is an initial sequence FIGURE 1. Diagram of brain and taste metabotropic glutamate receptor 1 that is not translated. No traditional ATG codon to indicate (mGluR1) structure. The brain type contains a long extracellular binding initiation of translation was found near by the stop codon (40). domain (NTD), a cysteine-rich region (CR), the 7-spanning transmembrane domain (TMD), and a long amino acid sequence inside the cytoplasm. The The closest methionine resided one exon away from the stop taste type mGluR1 conserves only part of the Venus flytrap binding domain codon, which would result in an excessively long untranslated (white boxes), but the CR and TMD are identical to the brain mGluR1. TASTE METABOTROPIC GLUTAMATE RECEPTOR TYPE 1 745S tongue, where T1R3 is mostly co-expressed with T1R2 (21). All together, truncated mGluR1 can potentially function as an umami taste receptor in rats. However, more in vitro studies are needed to characterize the receptor further, and more in vivo studies are needed to evaluate how knocking out mGluR1 may affect ingestive behavior, particularly umami preference. (Other articles in this supplement to the Journal include references 42–70.)

The authors’ responsibilities were as follows—ASG: designed the study, reviewed the literature, wrote the manuscript, and collected, prepared, and analyzed the data; TM: designed the molecular biology studies, analyzed the data, and provided significant advice about the writing of the manuscript; HU: offered support and supervision for the design and conduct of the Downloaded from https://academic.oup.com/ajcn/article/90/3/743S/4597174 by guest on 27 September 2021 Xenopus expression system and obtained funding for the purchase of animals and materials for the initial study; and KT: participated in the design and supervision of the study with valuable financial support for the purchase of equipment. The authors are employees of Ajinomoto Co, Inc, which supported this work, and are inventors of a patent filed with the European Patent Office and the US Patent and Trademark Office (WO03/068818). The patent has been licensed to the Ajinomoto Company. Ajinomoto is a manufacturer of food and amino acids including glutamate.

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