TRPM Related Drug Discovery Products

The eight members of the human TRPM subfamily, which was founded by the protein melastatin (TRPM1), can be divided into four pairs: TRPM1 and TRPM3; TRPM2 and TRPM8; TRPM4 and TRPM5; and TRPM6 and TRPM7. The six anticipated transmembrane segments of the TRPM subfamily, which are flanked by cytoplasmic N- and C-terminal tails, have several structural characteristics with voltage-gated channels. Four lengths of amino acids with some sequence similarity can be found in the N-terminal portions of TRPMs, however these do not correspond to any known structural motifs, and it is still unclear what these amino acid stretches accomplish. The structure and length of the C-terminal sequences in the TRPM family differ.

Fig.1. Ion permeabilities of TRP channels.^1,2

Creative Biolabs is a world-leading provider in membrane protein drug discovery and we can offer TRPM related drug discovery tools for our clients:

• TRPM Assays
• Ion Channel Cell Lines
• Ion Channel Membranes
• Membrane Protein Tools

Overview of TRPM

• TRPM1

It has been suggested that TRPM1 is a Ca²⁺ channel that is constitutively active. However, it is not immediately clear how a constitutively active Ca²⁺ channel slows down melanoma cells' pace of proliferation. It's possible that channel expression is a result of the growth behavior rather than its primary cause. As an alternative, the channel might not result in Ca²⁺ influx but rather increase intracellular Ca²⁺ ([Ca²⁺]i) concentration through an unidentified mechanism.

• TRPM2

Although TRPM2 channels are mostly found in the brain, they have also been found in the bone marrow, spleen, heart, leukocytes, liver, and lung. Whole-cell, linear currents generated by TRPM2 channels have a reversal potential of ~0 mV. The channels are permeable to Ca²⁺ and convey monovalent cations like Na⁺, K⁺, and Cs⁺. Ca²⁺ does not by itself activate TRPM2 channels, although an increase in [Ca²⁺]i makes activation easier by making the channels more sensitive to ADP-ribose.

• TRPM3

TRPM3 has not been found in mouse kidney, however it is largely found in the human kidney and brain. The removal and readmission of extracellular Ca²⁺ result in a drop and an increase in [Ca²⁺]i, respectively. TRPM3 promotes higher basal levels of [Ca²⁺]i. TRPM3 is thought to have a role in renal Ca²⁺ homeostasis based on its constitutive activity, which is boosted by extracellular hypotonicity, and its capacity to penetrate Ca²⁺. It is unknown if the activity caused by osmosis is communicated as a physical stimulus or if it is a byproduct of messengers produced by hypotonicity. As a result, it is feasible that TRPM3 channels may be controlled by other mechanisms outside of osmotic fluctuations.

• TRPM4

TRPM4 can be found in both electrically excitable and non-excitable cells as well as many other tissues and cell types. Initially, TRPM4 was identified as a 1040-residue plasma membrane protein that was predicted to be a constitutively active, Ca²⁺-permeable channel based on fluorescence data. But later research on the 1214-residue full-length TRPM4 identified the protein as a Ca²⁺-activated, nonselective (CAN) cation channel.

• TRPM5

During a functional examination of a chromosomal area linked to numerous cancers, the gene encoding TRPM5 was discovered. Monovalent-specific ion channels TRPM4, TRPM5, with a conductance of 25 pS, do not pore Ca²⁺. The channel has a linear current-voltage relationship, but because TRPM5's voltage-dependent modulation of open probability is comparable to that of TRPM4's, TRPM5 currents exhibit substantial outward rectification in steady-state relationships with voltage.

• TRPM6

TRPM6's chemical makeup and electrophysiological characteristics are quite similar to those of TRPM7. TRPM6-mediated currents are nearly identical to TRPM7-mediated currents in cells that only express TRPM6; both are activated by a decrease in free Mg²⁺ and Mg-ATP and have the same current-voltage relationship and selectivity for Ca²⁺ and Mg²⁺.

• TRPM7

Increasing intracellular ATP concentrations activates TRPM7, a Ca²⁺-permeable, nonselective cation channel with a single-channel conductance of 105 pS. High intracellular quantities of free Mg²⁺ and Mg-ATP significantly inhibit TRPM7.

• TRPM8

TRPM8 was initially discovered to be a gene restricted to the prostate, but it was later discovered to be present in a subgroup of cold-responsive dorsal root ganglia neurons as well as in trigeminal ganglia neurons. Although TRPM8's purpose in the prostate is unknown, its presence in cells that are sensitive to cold suggests that it may play a part in thermosensation and nociception.

References

1. Ciaglia, Tania, et al. "On the modulation of TRPM channels: Current perspectives and anticancer therapeutic implications." Frontiers in Oncology 12 (2023): 1065935.
2. Distributed under Open Access License CC BY 4.0. The original image was modified by extracting and using part b and the title was changed to " Ion permeabilities of TRP channels.