Negatively Charged Amino Acids Near and in Transient Receptor Potential (TRP) Domain of TRPM4 Channel Are One Determinant of Its Ca2+ Sensitivity

Yamaguchi, Soichiro; Tanimoto, Akira; Otsuguro, Ken-ichi; Hibino, Hiroshi; S, Itó

doi:10.1074/jbc.m114.606087

Cited by 21 publications

(27 citation statements)

References 53 publications

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“…The C-terminal end of the TRP helix 1 is positioned right underneath the S1-S4 domain with Glu1064 and Arg1068 pointing their side chains into the intracellular-facing cavity. Glu1064 was shown to be important for Ca 2+ activation 41 and we suspect the cavity could potentially house the Ca 2+ binding site. TRP helix 2 and the loop between the two TRP helices are buried in the lower leaflet of the membrane; the loop also participates in the formation of the cavity with S1-S4 by patching the side opening.…”

Section: Resultsmentioning

confidence: 92%

Structures of the calcium-activated, non-selective cation channel TRPM4

Guo

She

Zeng

et al. 2017

Nature

171

196

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TRPM4 is a calcium-activated, phosphatidylinositol bisphosphate (PtdInsP2) modulated, non-selective cation channel, and belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the cryo-EM structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide binding domain (NBD) and the C-terminal coiled coil participate in the tetrameric assembly of the channel; ATP binds at NBD and inhibits channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. S1-S4 domain and post-S6 TRP domain form the central gating apparatus that likely house the Ca2+ and PtdInsP2 binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and also reveal the molecular architecture of the TRPM family for the first time.

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Section: Resultsmentioning

confidence: 92%

Structures of the calcium-activated, non-selective cation channel TRPM4

Guo

She

Zeng

et al. 2017

Nature

171

196

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“…A previous mutagenesis study showed that the Glu1068Gln mutation significantly reduces TRPM4 Ca 2+ -sensitivity (17). Glu1068 is located in the pathway leading to the Ca 2+ -binding site from the cytoplasmic space (fig.…”

mentioning

confidence: 99%

Structure of the human TRPM4 ion channel in a lipid nanodisc

Autzen

Myasnikov

Campbell

et al. 2018

Science

234

248

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Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage dependent manner, but unlike many other TRP channels is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3Å resolution as determined by single particle electron cryo-microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium binding site within the intracellular side of the S1–S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.

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“…Formation of colloidal aggregates has been shown to be an important determinant of the biochemical activity of many "soluble" molecules at their biologic targets (Duan et al, 2015), which may be relevant to TRPM8, as well as TRPV1 and TRPA1 activation by particles. In support of TRPM8 activation by soluble calcium, TRPM2, M4, and M5 are activated by intracellular calcium ion binding at specific residues (Liman, 2007;Du et al, 2009;Yamaguchi et al, 2014). However, this has not been shown for TRPM8 thus far, and as described earlier, high (.2 mM) extracellular calcium may inhibit TRPM8.…”

Section: Discussionmentioning

confidence: 83%

Activation of Human Transient Receptor Potential Melastatin-8 (TRPM8) by Calcium-Rich Particulate Materials and Effects on Human Lung Cells

Lamb

Romero

et al. 2017

Mol Pharmacol

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To better understand how adverse health effects are caused by exposure to particulate materials, and to develop preventative measures, it is important to identify the properties of particles and molecular targets that link exposure with specific biologic outcomes. Coal fly ash (CFA) is a by-product of coal combustion that can affect human health. We report that human transient receptor potential melastatin-8 (TRPM8) and an N-terminally truncated TRPM8 variant (TRPM8-Δ801) are activated by CFA and calcium-rich nanoparticles and/or soluble salts within CFA. TRPM8 activation by CFA was potentiated by cold temperature involving the phosphatidylinositol 4,5-bisphosphate binding residue (L1008), but was independent of the icilin and menthol binding site residue Y745 and, essentially, the N-terminal amino acids 1-800. CFA, calcium nanoparticles, and calcium salts also activated transient receptor potential vanilloid-1 (TRPV1) and transient receptor potential ankyrin-1 (TRPA1), but not TRPV4. CFA treatment induced CXCL1 and interleukin-8 mRNA in BEAS-2B and primary human bronchial epithelial cells through activation of both TRPM8 and TRPV1. However, neither mouse nor rat TRPM8 was activated by these materials, and knockout had no effect on cytokine induction in the lungs of CFA-instilled mice. Amino acids S921 and S927 in mouse were identified as important for the lack of response to CFA. These results imply that TRPM8, in conjunction with TRPV1 and TRPA1, might sense selected forms of inhaled particulate materials in human airways, shaping cellular responses to these materials, and improving our understanding of how and why certain particulate materials elicit different responses in biologic systems, affecting human health.

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Negatively Charged Amino Acids Near and in Transient Receptor Potential (TRP) Domain of TRPM4 Channel Are One Determinant of Its Ca2+ Sensitivity

Cited by 21 publications

References 53 publications

Structures of the calcium-activated, non-selective cation channel TRPM4

Structures of the calcium-activated, non-selective cation channel TRPM4

Structure of the human TRPM4 ion channel in a lipid nanodisc

Activation of Human Transient Receptor Potential Melastatin-8 (TRPM8) by Calcium-Rich Particulate Materials and Effects on Human Lung Cells

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