TRPM1 (transient receptor potential cation channel, subfamily M, member 1)

2009-02-01   Sulochana Devi , Vijayasaradhi Setaluri 

University of Wisconsin, School of Medicine, Public Health, Department of Dermatology, 439 Medical Science Centre, 1300 University Avenue, Madison, Wisconsin, 53706, USA

Identity

HGNC
LOCATION
15q13.3
LOCUSID
ALIAS
CSNB1C,LTRPC1,MLSN1

DNA/RNA

Description

The TRPM1 gene consists of 27 exons, spans at least 58 kb genomic DNA, on chromosome 7 in mouse.
In humans, the chromosomal localization of TRPM1 is on chromosome 15q13.3 region from 29080845 to 29181216 on the reverse strand. The TRPM1 gene encodes a 5.4kb (5428bp) mRNA transcript (Hunter et al., 1998; Fang and Setaluri, 2000). The promoter region of this gene contains 4 consensus binding sites for the microphthalmia-associated transcription factor (MITF), one of those binding site includes an M box, a motif shared by pigmentation genes (Hunter et al., 1998; Miller et al., 2004; Zhiqi et al., 2004). A 1-kb PvuII fragment from this region is capable of driving reporter gene expression in mouse and human melanoma cells.

Transcription

5.4 kb mRNA (full length transcript) with open reading frame of 4.812 (NT 129 to NT 4940, GenBank Accession No. NM_002420). Northern hybridization studies showed the presence of multiple short transcripts (1.8kb, 4kb, and 5.4kb) in human melanocytes as well as pigmented metastatic melanoma cell lines. However the full length mRNA is detectable only in melanocytes. (Fang and Setaluri, 2000).

Pseudogene

No pseudogenes for TRPM1 have been identified.

Proteins

Note

The open reading frame of TRPM1 (from NT 129-4940), encodes 1603 aa protein of predicted molecular mass ~182kDa. Cloning of full length human cDNA TRPM1 (GenBank Accession No. AF071787, with open reading frame from NT321- NT4922) resulted in 1533 aa protein product (Hunter et al., 1998; Fang and Setaluri, 2000). The shorter N-terminal isoform, TRPM1 (MLSN1-S), lacking the transmembrane domains, encodes for 500 aa protein (Fang and Setaluri, 2000). Rabbit polyclonal antibodies generated against the N-terminal part of TRPM1 detected proteins with molecular weights of 120 kDa and several minor bands ranging from 35 to 240kDa, including a doublet at 45kDa in primary neonatal melanocytes (Zhiqi et al., 2004).

Regulation of TRPM1: Short form of TRPM1 interacts directly and suppress the activity of full length form of TRPM1 (MLSN1-L), preventing its translocation to the plasma membrane (Xu et al., 2001), representing a mode of regulation of the channel activities. Presence of multiple isoforms of TRPM1 in normal melanocytes as well as pigment cell melanoma treated with a pharmacological agent suggests that TRPM1 can be regulated at the level of both transcription and mRNA processing (Fang and Setaluri, 2000). MITF is shown to be a major transcriptional regulator of TRPM1 expression through its interaction within the proximal promoter region (Miller et al., 2004; Zhiqi et al., 2004). Transfection of p53 or induction of endogenous p53 in melanocytes by ultraviolet (UV) radiation represses TRPM1 accompanied by decreased mobilization of intracellular Ca2+ and decreased extracellular Ca2+ uptake, indicating the role of p53 in TRPM1 regulation (Devi et al., 2007).

Description

TRPM1 is alternatively spliced and the splice variants are strongly depending on the cell type. Northern blot and RT-PCR analysis showed that the alternative splicing of TRPM1 mRNA produces short TRPM1 mRNAs derived from the 5 or 3 ends of the full length TRPM1. One of the major isoforms is predicted to encode a short protein (MLSN1-S) that includes only the N-terminal segment but not any transmembrane domain and is incapable of functioning independently as an ion channel.

Expression

TRPM1 is expressed exclusively in pigmented cells of the skin and the eyes.

Localisation

Isoforms of TRPM1 is mostly likely located on plasma membrane. Of the two major isoforms of TRPM1, L form (MLSN1-L) is localized on the cell membrane and the S form (MLSN1-S) is localized in the cytoplasm (Xu et al., 2001).

Function

TRPM1, transfected in heterologous HEK293T cells, acts as a calcium channel protein. The shorter isoform of TRPM1 has a regulatory effect on longer isoform, potentially suppresses the transport of longer isoform to cell membrane (Xu et al., 2001). Role of TRPM1 in cellular differentiation and proliferation was reported in human pigmented melanoma cell lines treated with hexamethylene bisacetamide (HMBA), were the expression of TRPM1 is upregulated (Fang and Setaluri, 2000). Lentiviral shRNA mediated knockdown of TRPM1 resulted in reduced intracellular Ca2+ and decreased Ca2+ uptake suggesting a role of TRPM1 in Ca2+ uptake by melanocytes (Devi et al., 2007).

Homology

Sequence similarity analysis revealed a limited homology to TRP family of calcium channel proteins and ~45% identity within the first 1200 amino acids of C.elegans (Prawitt et al., 2000).

Mutations

Note

Several single nucleotide polymorphisms have been identified but none of them is shown to be associated with any disease.

Implicated in

Entity name
Melanoma
Note
The exact role of TRPM1 in melanoma is not known.
Disease
Homogeneous TRPM1 mRNA expression in primary cutaneous melanoma correlates with prolonged disease free survival, and with the progression of the tumor, the TRPM1 is diminished or completely abolished in metastatic melanoma (Duncan et al., 1998; Duncan et al., 2001; Deeds et al., 2000; Miller et al., 2004). Reduced expression of TRPM1 gene in the retina of homozygous appaloosa horses with CSNB (congenital stationary night blindness) and coat spotting patterns compared to non appaloosa horses suggests a role for TRPM1 in normal night vision and melanogenesis (Bellone et al., 2008).
Prognosis
Down regulation/suppression of TRPM1 expression correlates with tumor progression. Decreased expression or absence of TRPM1 is a marker of poor prognosis and overall survival of melanoma patients.

Breakpoints

Note

No break points described so far.

Bibliography

Pubmed IDLast YearTitleAuthors
186605332008Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus).Bellone RR et al
112088522001Melastatin expression and prognosis in cutaneous malignant melanoma.Duncan LM et al
111124172000Expression and Up-regulation of alternatively spliced transcripts of melastatin, a melanoma metastasis-related gene, in human melanoma cells.Fang D et al
98068361998Chromosomal localization and genomic characterization of the mouse melastatin gene (Mlsn1).Hunter JJ et al
147447632004Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma.Miller AJ et al
118645972002A unified nomenclature for the superfamily of TRP cation channels.Montell C et al
152200022004Novel aspects of signaling and ion-homeostasis regulation in immunocytes. The TRPM ion channels and their potential role in modulating the immune response.Perraud AL et al
106078312000Identification and characterization of MTR1, a novel gene with homology to melastatin (MLSN1) and the trp gene family located in the BWS-WT2 critical region on chromosome 11p15.5 and showing allele-specific expression.Prawitt D et al
115358252001Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.Xu XZ et al
155773222004Human melastatin 1 (TRPM1) is regulated by MITF and produces multiple polypeptide isoforms in melanocytes and melanoma.Zhiqi S et al

Other Information

Locus ID:

NCBI: 4308
MIM: 603576
HGNC: 7146
Ensembl: ENSG00000134160

Variants:

dbSNP: 4308
ClinVar: 4308
TCGA: ENSG00000134160
COSMIC: TRPM1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000134160ENST00000256552Q7Z4N2
ENSG00000134160ENST00000397795Q7Z4N2
ENSG00000134160ENST00000542188Q7Z4N2
ENSG00000134160ENST00000558445H0YKU7
ENSG00000134160ENST00000558768A0A0A0MTQ9
ENSG00000134160ENST00000559177H0YM61
ENSG00000134160ENST00000559179Q7Z4N2
ENSG00000134160ENST00000560658Q7Z4N2
ENSG00000134160ENST00000560801A0A0A0MTR0

Expression (GTEx)

0
1
2
3
4

Pathways

PathwaySourceExternal ID
Transmembrane transport of small moleculesREACTOMER-HSA-382551
Ion channel transportREACTOMER-HSA-983712
Stimuli-sensing channelsREACTOMER-HSA-2672351
TRP channelsREACTOMER-HSA-3295583

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
198961132009TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness.87
198961092009Mutations in TRPM1 are a common cause of complete congenital stationary night blindness.81
194360592009TRPM1 forms ion channels associated with melanin content in melanocytes.74
198789172009Recessive mutations of the gene TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness in humans.67
147447632004Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma.59
218321822011TRPM1 forms complexes with nyctalopin in vivo and accumulates in postsynaptic compartment of ON-bipolar neurons in mGluR6-dependent manner.44
208467192010TRPM1: a vertebrate TRP channel responsible for retinal ON bipolar function.40
203005652010TRPM1 mutations are associated with the complete form of congenital stationary night blindness.39
281127292017Structural basis of dual Ca<sup>2+</sup>/pH regulation of the endolysosomal TRPML1 channel.33
237143222013Genotype and phenotype of 101 dutch patients with congenital stationary night blindness.29

Citation

Sulochana Devi ; Vijayasaradhi Setaluri

TRPM1 (transient receptor potential cation channel, subfamily M, member 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-02-01

Online version: http://atlasgeneticsoncology.org/gene/42707/trpm1