The TRPM ion channel subfamily: molecular, biophysical and functional features

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Significant progress in the molecular and functional characterization of a subfamily of genes that encode melastatin-related transient receptor potential (TRPM) cation channels has been made during the past few years. This subgroup of the TRP superfamily of ion channels contains eight mammalian members and has isoforms in most eukaryotic organisms. The individual members of the TRPM subfamily have specific expression patterns and ion selectivity, and their specific gating and regulatory mechanisms are tailored to integrate multiple signaling pathways. The diverse functional properties of these channels have a profound effect on the regulation of ion homoeostasis by mediating direct influx of Ca2+, controlling Mg2+ entry, and determining the potential of the cell membrane. TRPM channels are involved in several physiological and pathological conditions in electrically excitable and non-excitable cells, which make them exciting targets for drug discovery.

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Molecular features

The human TRPM subfamily was named from the founding member melastatin (TRPM1) and consists of eight members that can be grouped into four pairs (TRPM1 and TRPM3; TRPM2 and TRPM8; TRPM4 and TRPM5; and TRPM6 and TRPM7). The overarching structural elements of the TRPM subfamily are similar to those of voltage-gated channels, comprising six predicted transmembrane segments flanked by cytoplasmic N-terminal and C-terminal tails (Figure 2). The N-terminal regions of the TRPMs contain four stretches

TRPM1

Melastatin was identified originally in melanoma cells, where it appears to be a tumor suppressor that is downregulated in highly metastatic cells [17]. For this reason, assessment of melastatin mRNA in primary cutaneous tumors is a prognostic marker for metastasis in patients with localized malignant melanoma 18, 19. Currently, there is one report in which TRPM1 channels been assayed functionally (but not electrophysiologically) in a heterologous expression system [20]. HEK-293 cells that

TRPM2

TRPM2 channels are expressed primarily in the brain, but are detected in many other tissues, including bone marrow, spleen, heart, leukocytes, liver and lung. Native TRPM2 currents have been reported in the U937 monocyte cell line [7], neutrophils [21], microglia [22] and CRI-G1 insulinoma cells [23]. When expressed in HEK-293 cells, TRPM2 channels can be activated by elevating the intracellular concentration of ADP-ribose 7, 8, 9. The binding site of ADP-ribose is part of the Nudix enzymatic

TRPM3

This protein occurs primarily in kidney and brain in humans but is not detected in mouse kidney 31, 32. Functional data for TRPM3 channels are limited to two reports in which the protein has been expressed in a heterologous system 31, 32. The two constructs used in these studies differ in length (1325 and 1555 residues), which indicates that there might be alternatively spliced variants of TRPM3. TRPM3 induces elevated basal levels of [Ca2+]i, and removal and readmission of extracellular Ca2+

TRPM4

This channel occurs in many tissues and cell types, including electrically excitable and non-excitable cells (e.g. heart and skeletal muscle, neurons, thymocytes and liver cells). Initially, TRPM4 was described as a plasma membrane protein of 1040 residues and, based on fluorescence measurements, it was proposed to be a constitutively active, Ca2+-permeable channel [20]. However, subsequent work on the 1214-residue, full-length TRPM4 (designated TRPM4b to distinguish it from the shorter TRPM4a

TRPM5

The gene that encodes TRPM5 was identified during functional analysis of a chromosomal region that is associated with several tumors [41]. However, it is not clear whether the channel causes tumorigenesis. Northern analyses of the expression patterns of TRPM5 yield discrepant results: one study found that expression is limited primarily to tissues involved with taste [42], whereas another found a broader distribution in several fetal and adult tissues from humans and mice [41]. In functional

TRPM6

The molecular structure and electrophysiological properties of TRPM6 are related closely to those of TRPM7. Two studies that have characterized TRPM6 electrophysiologically 16, 47 reveal an interesting puzzle. In cells that express TRPM6 alone, one study demonstrates that large, TRPM6-mediated currents are essentially indistinguishable from TRPM7-mediated currents; both are activated by a reduction in free Mg2+ and Mg·ATP, and exhibit the same current–voltage relationship and selectivity for Ca

TRPM7

Two studies that characterized TRPM7 initially arrived at different conclusions about the activation mechanism and electrophysiological properties of this channel. One report classified it as a Ca2+-permeable, nonselective cation channel with a single-channel conductance of 105 pS (at +40 – +100 mV) that is activated by increasing intracellular ATP concentrations [12], and proposed that the kinase domain controlled the gating of TRPM7. A parallel study proposed that TRPM7 is a constitutively

TRPM8

TRPM8 was identified originally as a prostate-specific gene [59], but was later found to be present in a subset of cold-responsive dorsal root ganglia neurons and in neurons from trigeminal ganglia 60, 61. Although the function of TRPM8 in the prostate is unknown, its presence in cold-responsive cells is consistent with a role in thermosensation and nociception [62]. Indeed, heterologously expressed TRPM8 channels are activated by cooling cells to ≤24°C and by cooling agents such as menthol and

Concluding remarks

Based on significant progress achieved during the past few years, we have a reasonably good understanding of the molecular and biophysical properties of most TRPM proteins. These represent a heterogeneous group of ion channels that are characterized by specific expression patterns, selectivities and activation mechanisms. Unlike other TRP subfamilies, whose members are thought to function primarily as Ca2+-entry pathways, several TRPM channels are either impermeable to Ca2+ or function as

Acknowledgements

This work was supported by grants R01-GM065360 to A.F. and R01-NS040927 and R01-GM63954 to R.P.

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