Alternative titles; symbolsLONG TRANSIENT RECEPTOR POTENTIAL CHANNEL 5; LTRPC5MLSN1- AND TRP-RELATED GENE 1; MTR1HGNC Approved Gene Symbol: TRPM5Cytogenetic loca...
Alternative titles; symbols
HGNC Approved Gene Symbol: TRPM5
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:2,403,961-2,444,513 (from NCBI)
TRPM5 belongs to the melastatin (TRPM1; 603576)-related transient receptor (TRPM) channel family. TRPMs are Ca(2+)-permeable cation channels localized predominantly to the plasma membrane. The structural machinery of TRPM channels includes intracellular N and C termini, 6 transmembrane segments, and a pore region between segments 5 and 6. The N-terminal domain has a conserved region, and the C-terminal domain contains a TRP motif, a coiled-coil region, and, in some TRPM channels, an enzymatic domain. TRPM5 is implicated in enhancing TRPA1 (604775) expression and may be involved in regulating insulin secretion (review by Farooqi et al., 2011).
▼ Cloning and Expression
To identify candidate genes for 11p15.5-related diseases, Prawitt et al. (2000) compared human genomic sequence with expressed sequence tag and protein databases from different organisms to discover evolutionarily conserved sequences. They described the identification and characterization of a novel human transcript related to a putative Caenorhabditis elegans protein and the transient receptor potential (trp) gene (TRPC1; 602343). The highest homologies were observed with the human TRPC7 gene (603749) and with melastatin-1 (TRPM1), whose transcript is downregulated in metastatic melanomas. Other genes related to and interacting with the trp family include the PKD1 (601313) and PKD2 (173910) genes, involved in polycystic kidney disease. The novel gene presented by Prawitt et al. (2000) was named MTR1 for 'MLSN1- and TRP-related gene-1.' MTR1 was expressed as a 4.5-kb transcript in a variety of fetal and adult tissues. The putative open reading frame encodes 2 possible proteins of 872 or 1,165 amino acids, with several predicted membrane-spanning domains in both versions, due to alternative splicing. RT-PCR analysis of somatic cell hybrids harboring a single human chromosome 11 demonstrated exclusive expression of MTR1 in cell lines carrying a paternal chromosome 11, indicating allele-specific inactivation of the maternal copy by genomic imprinting.
Perez et al. (2002) used differential screening of cDNAs from individual mouse taste receptor cells to identify candidate taste transduction elements. Among the differentially expressed clones, one encoded Trpm5. In situ hybridization detected Trpm5 expression restricted to mouse taste tissue. In taste cells, Trpm5 was coexpressed with taste-signaling molecules such as alpha-gustducin (139395), G protein gamma-13 subunit, phospholipase C-beta-2 (PLCB2; 604114), and inositol 1,4,5-trisphosphate receptor type III (147267).
By RT-PCR, Prawitt et al. (2003) detected TRPM5 expression in several human and rodent cell lines, including murine neuronal cells, Burkitt lymphoma cells, murine B-lymphoma cells, HeLa cells, murine pancreatic beta cells, rat beta cells, and human pancreatic islets. No endogenous TRPM5 was detected in human embryonic kidney (HEK)-293 cells.
▼ Gene Function
By electrophysiologic recordings of CHO cells and X. laevis oocytes expressing Trpm5, Perez et al. (2002) determined that Trpm5 functions as a cationic channel that is gated when internal calcium stores are depleted. They proposed that Trpm5 may be responsible for capacitative calcium entry in taste receptor cells that respond to bitter and/or sweet compounds.
Prawitt et al. (2003) characterized the functional properties of heterologously expressed human TRPM5 in HEK-293 cells. TRPM5 displayed characteristics of a calcium-activated, nonselective cation channel that carried Na+, K+, and Cs+ ions equally well, but not Ca(2+) ions. TRPM5 was directly activated by intracellular Ca(2+) concentrations in the 0.3 to 1.0 micromolar range, whereas higher concentrations were inhibitory, resulting in a bell-shaped dose-response curve. TRPM5 channels activated and deactivated rapidly even during sustained elevations in intracellular Ca(2+) concentrations. TRPM5 required rapid changes in intracellular Ca(2+) concentration to generate significant whole-cell currents, whereas a slow increase in intracellular Ca(2+) concentration was ineffective. In a rat pancreatic beta cell line, an outwardly rectifying Trpm5-like current was induced by high intracellular Ca(2+) concentration. Since TRPM5 has been detected in both pancreatic beta cells and taste cells, Prawitt et al. (2003) concluded that TRPM5 may couple intracellular Ca(2+) release to electrical activity and subsequent cellular responses.
Talavera et al. (2005) showed that TRPM5 is a highly temperature-sensitive, heat-activated channel: inward TRPM5 currents increase steeply at temperature between 15 and 35 degrees C. TRPM4 (606936), a close homolog of TRPM5, showed similar temperature sensitivity. Heat activation was due to a temperature-dependent shift of the activation curve, in analogy to other thermosensitive TRP channels. Moreover, Talavera et al. (2005) showed that increasing temperature between 15 and 35 degrees C markedly enhanced the gustatory nerve response to sweet compounds in wildtype but not in Trpm5 knockout mice. The strong temperature sensitivity of TRPM5 may underlie effects of temperature on perceived taste in humans, including enhanced sweetness perception at high temperatures and 'thermal taste,' the phenomenon whereby heating or cooling of the tongue evokes sensations of taste in the absence of tastants.
Miller et al. (2018) described in detail an epithelial subset of mouse thymic cells that is remarkably similar to peripheral tuft cells that are found at mucosal barriers. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway genes and Il25 (605658). However, they are unique in their spatial association with cornified aggregates, ability to present antigens, and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire (607358)-expressing stage and depend on a known Aire-binding partner, Hipk2 (606868), for their development. Notably, the taste chemosensory protein Trpm5 is required for their thymic function, through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, Il4 (147780). Miller et al. (2018) concluded that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a nonredundant role in shaping thymic function.
▼ Gene Structure
Prawitt et al. (2000) determined that the MTR1 gene contains 24 exons.
By genomic sequence analysis, Prawitt et al. (2000) mapped the MTR1 gene between the TSSC4 (603852) and KVLQT1 (607542) genes on 11p15.5, within the Beckwith-Wiedemann syndrome critical region-1 (see 602631).
▼ Animal Model
Zhang et al. (2003) demonstrated that knockout of Trpm5, a taste TRP ion channel, or Plcb2, a phospholipase C selectively expressed in taste tissue, in mice abolished sweet, amino acid, and bitter taste reception, but did not affect sour or salty tastes. Therefore, despite relying on different receptors, sweet, amino acid, and bitter transduction appeared to converge on common signaling molecules. Mice engineered to rescue PLCB2 function exclusively in bitter receptor-expressing cells responded normally to bitter tastants, but did not taste sweet or amino acid stimuli. The authors concluded that bitter is encoded independently of sweet and amino acids and that taste receptor cells are not broadly tuned across these modalities.
By infecting mice with a parasitic protozoan or a diverse set of parasitic worms, Howitt et al. (2016) showed that all the parasites increased tuft cell abundance in intestine. Trpm5 -/- mice had disrupted chemosensory signaling and failed to expand tuft cells, goblet cells, eosinophils, and type-2 innate lymphoid cells during parasite colonization. Reduced tuft cells in Trpm5 -/- mice resulted in reduced parasite-induced expression of Il25 (605658) and, consequently, reduced Il13 (147683) production by innate lymphoid cells. Howitt et al. (2016) concluded that intestinal tuft cells are critical sentinels in gut epithelium that promote type-2 immunity in response to intestinal parasites.
All proteins of the transient receptor potential (TRP) channel family display topology of 6 transmembrane segments that is shared with some voltage-gated channels and the cyclic nucleotide-gated channels. The TRP channels can be divided on the basis of their homology into 3 TRP channel subfamilies: short (S), long (S), and osm (O). Harteneck et al. (2000) suggested that this subdivision also can be made according to channel function. Thus, the STRPC family, which includes Drosophila TRP and TRPL and the mammalian homologs TRPC1-7, is a family of calcium-permeable cation channels that are activated subsequent to receptor-mediated stimulation of different isoforms of phospholipase C. Members of the OTRPC family are calcium-permeable channels involved in pain transduction (vanilloid and vanilloid-like receptors), epithelial calcium transport, and, at least in C. elegans, in chemo-, mechano-, and osmoregulation.