1.A.4.5.12 TrpM4 of 1213 aas and 6 TMSs. Calcium-activated non selective
cation channel that mediates membrane depolarization. While it is
activated by increases in intracellular Ca2+, it is impermeable to it. It does mediate transport of monovalent cations (Na+ > K+ > Cs+ > Li+),
leading to depolarize the membrane. It thereby plays a central role in the function of cardiomyocytes, neurons from entorhinal cortex, dorsal root and
vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells,
cochlea hair cells etc. It also participates in T-cell activation by modulating
Ca2+ oscillations after T lymphocyte activation (Demion et al. 2007). The structure has been determined by cryo EM both with and without ATP (Guo et al. 2017). It consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain to inhibit channel activity. TRPM4 has an exceptionally wide filter although it is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca2+- and PtdIns(4,5)P2-binding sites (Guo et al. 2017). TRPM4 currents are activated by micromolar concentrations of cytoplasmic Ca2+and progressively desensitized. Zhang et al. 2005 showed that desensitization can be explained by a loss of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) from the channels. TrpM4 interacts directly with glutamate N-methyl-D-aspartate receptor channels (NMDARs) to promote excitotoxicity. Small-molecule interface inhibitors prevent NMDAR-TRPM4 physical coupling and eliminate excitotoxicity. They are therefore neuroprotectants (Yan et al. 2020). Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex- and age-dependent manner in mice (Arullampalam et al. 2023).
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Accession Number: | Q7TN37 |
Protein Name: | Transient receptor potential cation channel subfamily M member 4 |
Length: | 1213 |
Molecular Weight: | 135760.00 |
Species: | Mus musculus (Mouse) [10090] |
Number of TMSs: | 5 |
Location1 / Topology2 / Orientation3: |
Cell membrane1 / Multi-pass membrane protein2 |
Substrate |
lithium(1+), sodium(1+), potassium(1+), caesium(1+) |
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1: MVGPEKEQSW IPKIFRKKVC TTFIVDLSDD AGGTLCQCGQ PRDAHPSVAV EDAFGAAVVT
61: EWNSDEHTTE KPTDAYGDLD FTYSGRKHSN FLRLSDRTDP ATVYSLVTRS WGFRAPNLVV
121: SVLGGSGGPV LQTWLQDLLR RGLVRAAQST GAWIVTGGLH TGIGRHVGVA VRDHQTASTG
181: SSKVVAMGVA PWGVVRNRDM LINPKGSFPA RYRWRGDPED GVEFPLDYNY SAFFLVDDGT
241: YGRLGGENRF RLRFESYVAQ QKTGVGGTGI DIPVLLLLID GDEKMLKRIE DATQAQLPCL
301: LVAGSGGAAD CLVETLEDTL APGSGGLRRG EARDRIRRYF PKGDPEVLQA QVERIMTRKE
361: LLTVYSSEDG SEEFETIVLR ALVKACGSSE ASAYLDELRL AVAWNRVDIA QSELFRGDIQ
421: WRSFHLEASL MDALLNDRPE FVRLLISHGL SLGHFLTPVR LAQLYSAVSP NSLIRNLLDQ
481: ASHASSSKSP PVNGTVELRP PNVGQVLRTL LGETCAPRYP ARNTRDSYLG QDHRENDSLL
541: MDWANKQPST DASFEQAPWS DLLIWALLLN RAQMAIYFWE KGSNSVASAL GACLLLRVMA
601: RLESEAEEAA RRKDLAATFE SMSVDLFGEC YHNSEERAAR LLLRRCPLWG EATCLQLAMQ
661: ADARAFFAQD GVQSLLTQKW WGEMDSTTPI WALLLAFFCP PLIYTNLIVF RKSEEEPTQK
721: DLDFDMDSSI NGAGPPGTVE PSAKVALERR QRRRPGRALC CGKFSKRWSD FWGAPVTAFL
781: GNVVSYLLFL LLFAHVLLVD FQPTKPSVSE LLLYFWAFTL LCEELRQGLG GGWGSLASGG
841: RGPDRAPLRH RLHLYLSDTW NQCDLLALTC FLLGVGCRLT PGLFDLGRTV LCLDFMIFTL
901: RLLHIFTVNK QLGPKIVIVS KMMKDVFFFL FFLCVWLVAY GVATEGILRP QDRSLPSILR
961: RVFYRPYLQI FGQIPQEEMD VALMIPGNCS MERGSWAHPE GPVAGSCVSQ YANWLVVLLL
1021: IVFLLVANIL LLNLLIAMFS YTFSKVHGNS DLYWKAQRYS LIREFHSRPA LAPPLIIISH
1081: VRLLIKWLRR CRRCRRANLP ASPVFEHFRV CLSKEAERKL LTWESVHKEN FLLAQARDKR
1141: DSDSERLKRT SQKVDTALKQ LGQIREYDRR LRGLEREVQH CSRVLTWMAE ALSHSALLPP
1201: GAPPPPSPTG SKD