. Luminal amino acid sensing in the rat gastric mucosa. Am J Physiol Gastrointest Liver Physiol 291: G1163-G1170, 2006. First published June 29, 2006 doi:10.1152/ajpgi.00587.2005.-Recent advancements in molecular biology in the field of taste perception in the oral cavity have raised the possibility for ingested nutrients to be "tasted" in the upper gastrointestinal tract. The purpose of this study was to identify the existence of a nutrient-sensing system by the vagus in the rat stomach. Afferent fibers of the gastric branch increased their firing rate solely with the intragastric application of the amino acid glutamate. Other amino acids failed to have the same effect. This response to glutamate was blocked by the depletion of serotonin (5-HT) and inhibition of serotonin receptor 3 (5-HT3) or nitric oxide (NO) synthase enzyme. Luminal perfusion with the local anesthesia lidocaine abolished the glutamate-evoked afferent activation. The afferent response was also mimicked by luminal perfusion with a NO donor, sodium nitroprusside. In addition, the NO donorinduced afferent activation was abolished by 5-HT 3 blockade as well. Altogether, these results strongly suggest the existence of a sensing system for glutamate in the rat gastric mucosa. Thus luminal glutamate would enhance the electrophysiological firing rate of afferent fibers from the vagus nerve of the stomach through the production of mucosal bioactive substances such as NO and 5-HT. Assuming there is a universal coexistence of free glutamate with dietary protein, a glutamate-sensing system in the stomach could contribute to the gastric phase of protein digestion.visceral nutrient sensing; rat vagal gastric afferent; serotonin; nitric oxide THE NUMBER OF ARTICLES DEDICATED to the abdominal vagus nerve that were focused in gut nutrient sensing has increased dramatically over the last decade (33,36,42). This is due to the advancement of techniques that facilitated the study of visceral afferent fibers and their function and characteristic electrophysiological patterns and also due to recognition that these fibers are important for body nutrient homeostasis. Psychophysiological approaches for the understanding of ingestive behavior have demonstrated that the presence of food in the upper gastrointestinal (GI) tract plays a critical role in determining meal size. The vagus nerve is extensively distributed throughout the GI tract, from the posterior region of oral cavity and esophagus to the lowest part of the colon, and functions as the primary neuroanatomical circuit in the gut-brain axis to transmit meal-related signals from the GI mucosa to the central nervous system. This is where regulatory processes (e.g., ingestive behavior, nutrient absorption, GI secretion, and stomach emptying) as well as conscious sensations (e.g., satiety, nausea, and discomfort) take place (5, 22, 37).Recently, it has been shown that taste transduction-related molecules, such as ␣-gustducin and a family of bitter-sensing taste receptors (T 2 Rs), were also expressed at the GI mu...

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Non-technical summary The distinctive umami taste elicited by L-glutamate and some other amino acids is thought to be initiated by G-protein-coupled receptors, such as heteromers of taste receptor type 1, members 1 and 3, and metabotropic glutamate receptors 1 and 4. We demonstrate the existence of multiple types of glutamate-sensitive gustatory nerve fibres and the contribution of multiple receptors and transduction pathways to umami taste. Such multiple systems for umami taste may differentially contribute to the behavioural preference for glutamate and discriminability of glutamate taste. AbstractThe distinctive umami taste elicited by L-glutamate and some other amino acids is thought to be initiated by G-protein-coupled receptors. Proposed umami receptors include heteromers of taste receptor type 1, members 1 and 3 (T1R1+T1R3), and metabotropic glutamate receptors 1 and 4 (mGluR1 and mGluR4). Multiple lines of evidence support the involvement of T1R1+T1R3 in umami responses of mice. Although several studies suggest the involvement of receptors other than T1R1+T1R3 in umami, the identity of those receptors remains unclear. Here, we examined taste responsiveness of umami-sensitive chorda tympani nerve fibres from wild-type mice and mice genetically lacking T1R3 or its downstream transduction molecule, the ion channel TRPM5. Our results indicate that single umami-sensitive fibres in wild-type mice fall into two major groups: sucrose-best (S-type) and monopotassium glutamate (MPG)-best (M-type). Each fibre type has two subtypes; one shows synergism between MPG and inosine monophosphate (S1, M1) and the other shows no synergism (S2, M2). In both T1R3 and TRPM5 null mice, S1-type fibres were absent, whereas S2-, M1-and M2-types remained. Lingual application of mGluR antagonists selectively suppressed MPG responses of M1-and M2-type fibres. These data suggest the existence of multiple receptors and transduction pathways for umami responses in mice. Information initiated from T1R3-containing receptors may be mediated by a transduction pathway including TRPM5 and conveyed by sweet-best fibres, whereas umami information from mGluRs may be mediated by TRPM5-independent pathway(s) and conveyed by glutamate-best fibres. Ami, amiloride; CPPG, (RS)-α-cyclopropyl-4-phosphonophenylglycine; CT, chorda tympani; ENaC, epithelial sodium channel; GAD67, glutamate decarboxylase 67; GL, glossopharyngeal; GMP, guanosine monophosphate; HEK, human embryonic kidney; IMP, inosine monophosphate; IP 3 R3, inositol 1,4,5-trisphosphate receptor 3; KO, knockout; L-Ala, L-alanine; L-AP4, L-(+)-2-amino-4-phosphonobutyrate; L-Arg, L-arginine hydrochloride; L-Cys, L-cysteine; L-Lys, L-lysine hydrochloride; mGluR1(mGluR4), metabotropic glutamate receptor type 1 (type 4); MPG, monopotassium glutamate; MSG, monosodium glutamate; NMDA, N -methyl-D-aspartic acid; QHCl, quinine hydrochloride; Quis, quisqualic acid; Suc, sucrose; TRPM5, transient receptor potential cation channel subfamily M member 5; WT, wild-type.

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L L-glutamate not only confers cognitive discrimination for umami taste in the oral cavity, but also conveys sensory information to vagal afferent fibers in the gastric mucosa. We used RT-PCR, western blotting, and immunohistochemistry to demonstrate that mGluR1 is located in glandular stomach. Double staining revealed that mGluR1 is found at the apical membrane of chief cells and possibly in parietal cells. Moreover, a diet with 1% L L-glutamate induced changes in the expression of pepsinogen C mRNA in stomach mucosa. These data suggest that mGluR1 is involved in the gastric phase regulation of protein digestion.

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l-Glutamate is a multifunctional amino acid involved in taste perception, intermediary metabolism, and excitatory neurotransmission. In addition, recent studies have uncovered new roles for l-glutamate in gut-brain axis activation and energy homeostasis. l-Glutamate receptors and their cellular transduction molecules have recently been identified in gut epithelial cells. Stimulation of such l-glutamate receptors by luminal l-glutamate activates vagal afferent nerve fibers and then parts of the brain that are targeted directly or indirectly by these vagal inputs. Notably, 3 areas of the brain-the medial preoptic area, the hypothalamic dorsomedial nucleus, and the habenular nucleus-are activated by intragastric l-glutamate but not by glucose or sodium chloride. Furthermore, the chronic, ad libitum ingestion of a palatable solution of monosodium l-glutamate (1% wt:vol) by rats has also been found to reduce weight gain, fat deposition, and plasma leptin concentrations compared with rats that ingest water alone. No difference in food intake was observed. Such effects may also be vagally mediated. Together, such findings contribute to the growing knowledge base that indicates that l-glutamate signaling via taste and gut l-glutamate receptors may influence multiple physiologic functions, such as thermoregulation and energy homeostasis.