TRPM6 N-Terminal CaM- and S100A1-Binding Domains

Transient receptor potential (TRPs) channels are crucial downstream targets of calcium signalling cascades. They can be modulated either by calcium itself and/or by calcium-binding proteins (CBPs). Intracellular messengers usually interact with binding domains present at the most variable TRP regions—N- and C-cytoplasmic termini. Calmodulin (CaM) is a calcium-dependent cytosolic protein serving as a modulator of most transmembrane receptors. Although CaM-binding domains are widespread within intracellular parts of TRPs, no such binding domain has been characterised at the TRP melastatin member—the transient receptor potential melastatin 6 (TRPM6) channel. Another CBP, the S100 calcium-binding protein A1 (S100A1), is also known for its modulatory activities towards receptors. S100A1 commonly shares a CaM-binding domain. Here, we present the first identified CaM and S100A1 binding sites at the N-terminal of TRPM6. We have confirmed the L520-R535 N-terminal TRPM6 domain as a shared binding site for CaM and S100A1 using biophysical and molecular modelling methods. A specific domain of basic amino acid residues (R526/R531/K532/R535) present at this TRPM6 domain has been identified as crucial to maintain non-covalent interactions with the ligands. Our data unambiguously confirm that CaM and S100A1 share the same binding domain at the TRPM6 N-terminus although the ligand-binding mechanism is different.

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Structural insights into TRPM8 inhibition and desensitization

Science ◽

10.1126/science.aax6672 ◽

2019 ◽

Vol 365 (6460) ◽

pp. 1434-1440 ◽

Cited By ~ 37

Author(s):

Melinda M. Diver ◽

Yifan Cheng ◽

David Julius

Keyword(s):

Conformational Changes ◽

Calcium Binding ◽

Transient Receptor Potential ◽

Trp Channels ◽

Receptor Potential ◽

Binding Pocket ◽

Chemical Structures ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Large Rearrangements

The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo–electron microscopy structures of TRPM8 in ligand-free, antagonist-bound, or calcium-bound forms, revealing how robust conformational changes give rise to two nonconducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and we delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.

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Abstract P153: Crosstalk Between Vascular Redox and Calcium Signalling in Hypertension Involves Transient Receptor Potential Melastatin 2 (TRPM2) Channel

Hypertension ◽

10.1161/hyp.72.suppl_1.p153 ◽

2018 ◽

Vol 72 (Suppl_1) ◽

Author(s):

Rhéure Alves-Lopes ◽

Karla B Neves ◽

Aikaterini Anagnostopoulou ◽

Silvia Lacchini ◽

Augusto C Montezano ◽

...

Keyword(s):

Transient Receptor Potential ◽

Calcium Signalling ◽

Receptor Potential ◽

Transient Receptor Potential Melastatin ◽

Trpm2 Channel ◽

Transient Receptor

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Regulation of calcium signalling by adenine-based second messengers

Biochemical Society Transactions ◽

10.1042/bst0350109 ◽

2007 ◽

Vol 35 (1) ◽

pp. 109-114 ◽

Cited By ~ 73

Author(s):

R. Fliegert ◽

A. Gasser ◽

A.H. Guse

Keyword(s):

Transient Receptor Potential ◽

Second Messengers ◽

Calcium Signalling ◽

Receptor Potential ◽

Cell Types ◽

Cellular Systems ◽

Membrane Receptors ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Plasma Membrane Receptors

cADPR [cyclic ADPR (ADP-ribose)], NAADP (nicotinic acid–adenine dinucleotide phosphate) and ADPR belong to the family of adenine-containing second messengers. They are metabolically related and are all involved in the regulation of cellular Ca2+ homoeostasis. Activation of specific plasma membrane receptors is connected to cADPR formation in many cell types and tissues. In contrast receptor-mediated formation of NAADP and ADPR has been shown only in a few selected cellular systems. The intracellular Ca2+ channel triggered by cADPR is the RyR (ryanodine receptor); in the case of NAADP, both activation of RyR and a novel Ca2+ channel have been proposed. In contrast, ADPR opens the non-specific cation channel TRPM2 [TRP (transient receptor potential) melastatin 2] that belongs to the TRP family of ion channels.

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The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn2+-binding domain essential for ligand binding and activity

10.1101/2022.01.04.474898 ◽

2022 ◽

Author(s):

Simon Sander ◽

Ellen Gattkowski ◽

Jelena Pick ◽

Ralf Fliegert ◽

Henning Tidow

Keyword(s):

Crystal Structure ◽

Transient Receptor Potential ◽

Specific Binding ◽

Receptor Potential ◽

Binding Domain ◽

Dependent Manner ◽

Structural Element ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Species Specific

Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable, non-selective cation channel involved in diverse physiological processes such as immune response, apoptosis and body temperature sensing. TRPM2 is activated by ADP-ribose (ADPR) and 2′-deoxy-ADPR in a Ca2+-dependent manner. While two species-specific binding sites exist for ADPR, a binding site for 2′-deoxy-ADPR is not known yet. Here, we report the crystal structure of the MHR1/2 domain of TRPM2 from zebrafish (Danio rerio) and show binding of both ligands to this domain. We identified a so-far unrecognized Zn2+-binding domain that was not resolved in previous cryo-EM structures and that is conserved in most TRPM channels. In combination with patch clamp experiments, we comprehensively characterize the effect of the Zn2+-binding domain on TRPM2 activation. Our results provide insight into a conserved structural element essential for channel activity.

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A9595 Crosstalk Between Vascular Redox and Calcium Signalling in Hypertension Involves Transient Receptor Potential Melastatin 2 Channel Activation

Journal of Hypertension ◽

10.1097/01.hjh.0000548217.61012.c0 ◽

2018 ◽

Vol 36 ◽

pp. e56

Author(s):

Rhéure Lopes ◽

Karla Neves ◽

Aikaterini Anagnostopoulou ◽

Silvia Lacchini ◽

Augusto C. Montezano ◽

...

Keyword(s):

Transient Receptor Potential ◽

Calcium Signalling ◽

Receptor Potential ◽

Channel Activation ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

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Inositol lipids and TRPC channel activation

Biochemical Society Symposium ◽

10.1042/bss2007c04 ◽

2007 ◽

Vol 74 ◽

pp. 37-45 ◽

Cited By ~ 12

Author(s):

James W. Putney

Keyword(s):

Plasma Membrane ◽

Phospholipase C ◽

Transient Receptor Potential ◽

Calcium Signalling ◽

Receptor Potential ◽

Breakdown Product ◽

Channel Activation ◽

Inositol Lipids ◽

Transient Receptor ◽

Secondary Mechanism

The original hypothesis put forth by Bob Michell in his seminal 1975 review held that inositol lipid breakdown was involved in the activation of plasma membrane calcium channels or ‘gates’. Subsequently, it was demonstrated that while the interposition of inositol lipid breakdown upstream of calcium signalling was correct, it was predominantly the release of Ca2+ that was activated, through the formation of Ins(1,4,5)P3. Ca2+ entry across the plasma membrane involved a secondary mechanism signalled in an unknown manner by depletion of intracellular Ca2+ stores. In recent years, however, additional non-store-operated mechanisms for Ca2+ entry have emerged. In many instances, these pathways involve homologues of the Drosophila trp (transient receptor potential) gene. In mammalian systems there are seven members of the TRP superfamily, designated TRPC1–TRPC7, which appear to be reasonably close structural and functional homologues of Drosophila TRP. Although these channels can sometimes function as store-operated channels, in the majority of instances they function as channels more directly linked to phospholipase C activity. Three members of this family, TRPC3, 6 and 7, are activated by the phosphoinositide breakdown product, diacylglycerol. Two others, TRPC4 and 5, are also activated as a consequence of phospholipase C activity, although the precise substrate or product molecules involved are still unclear. Thus the TRPCs represent a family of ion channels that are directly activated by inositol lipid breakdown, confirming Bob Michell's original prediction 30 years ago.

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Faculty Opinions recommendation of The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725063502.793517531 ◽

2016 ◽

Author(s):

André Strydom

Keyword(s):

Transient Receptor Potential ◽

Amyloid Β ◽

Receptor Potential ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Neurovascular Dysfunction

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The TRPM7 Channel in the Nervous and Cardiovascular Systems

Current Protein and Peptide Science ◽

10.2174/1389203721666200605170938 ◽

2020 ◽

Vol 21 (10) ◽

pp. 985-992 ◽

Cited By ~ 1

Author(s):

Koichi Inoue ◽

Zhi-Gang Xiong ◽

Takatoshi Ueki

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Kinase Domain ◽

Cellular Functions ◽

Transient Receptor Potential Melastatin ◽

Cation Permeability ◽

Cardiovascular Systems ◽

Transient Receptor ◽

Excitatory Responses ◽

Dual Operations

: Transient receptor potential melastatin 7 (TRPM7), along with the closely related TRPM6, are unique channels that have dual operations: cation permeability and kinase activity. In contrast to the limited tissue distribution of TRPM6, TRPM7 is widely expressed among tissues and is therefore implicated in a variety of cellular functions physiologically and pathophysiologically. The discovery of TRPM7’s unique structure imparting dual ion channel and kinase activities shed light onto novel and peculiar biological functions, such as Mg2+ homeostasis, cellular Ca2+ flickering, and even intranuclear transcriptional regulation by a cleaved kinase domain translocated to nuclei. Interestingly, at a higher level, TRPM7 participates in several biological processes in the nervous and cardiovascular systems, in which excitatory responses in neurons and cardiomyocytes are critical for their function. Here, we review the roles of TRPM7 in cells involved in the nervous and cardiovascular systems and discuss its potential as a future therapeutic target.

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Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study

Current Neurovascular Research ◽

10.2174/1567202617666200415142211 ◽

2020 ◽

Vol 17 (3) ◽

pp. 249-258 ◽

Cited By ~ 4

Author(s):

Pavan Thapak ◽

Mahendra Bishnoi ◽

Shyam S. Sharma

Keyword(s):

Cognitive Impairment ◽

Cognitive Deficits ◽

Ache Activity ◽

Transient Receptor Potential ◽

Mrna Level ◽

Receptor Potential ◽

Transient Receptor Potential Melastatin ◽

Trpm2 Channels ◽

Transient Receptor ◽

Gsk 3Β

Background: Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. Objective: The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Methods: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Results: : Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. Conclusion: : This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.

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