scholarly journals Gαq sensitizes TRPM8 to inhibition by PI(4,5)P2 depletion upon receptor activation

2018 ◽  
Author(s):  
Luyu Liu ◽  
Yevgen Yudin ◽  
Chifei Kang ◽  
Natalia Shirokova ◽  
Tibor Rohacs
Keyword(s):  
Plasma Membrane ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Receptor Activation ◽  
Gpcr Activation ◽  
Transient Receptor Potential Melastatin ◽  
Channel Inhibition ◽  
Direct Binding ◽  
Mouse Dorsal Root Ganglion ◽  
Transient Receptor

ABSTRACTActivation of G-protein coupled receptors (GPCRs) was proposed to inhibit the cold and menthol sensitive Transient Receptor Potential Melastatin 8 (TRPM8) channels via direct binding of Gαq to the channel. It is well documented that TRPM8 requires the plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2 or PIP2] for activity. It was claimed however that a decrease in cellular levels of this lipid does not contribute to channel inhibition upon receptor activation. Here we show that supplementing the whole cell patch pipette with PI(4,5)P2 reduced inhibition of TRPM8 by activation of Gαq-coupled receptors in mouse dorsal root ganglion (DRG) neurons. Activation of the same receptors induced Phospholipase C (PLC) activation and decreased plasma membrane PI(4,5)P2 levels in these neurons. PI(4,5)P2 also reduced inhibition of TRPM8 by activation of heterologously expressed Gαq-coupled muscarinic M1 receptors. Co-expression of a constitutively active Gαq protein that does not couple to PLC inhibited TRPM8 activity, and in cells expressing this protein decreasing PI(4,5)P2 levels using a voltage sensitive 5’-phosphatase induced a stronger inhibition of TRPM8 activity than in control cells. Our data indicate that PI(4,5)P2 depletion plays an important role in TRPM8 inhibition upon GPCR activation, and Gαq inhibits the channel by reducing its apparent affinity for PI(4,5)P2 and thus sensitizes the channel to inhibition by decreasing PI(4,5)P2 levels.

scholarly journals Transient Receptor Potential Melastatin 1 (TRPM1) Is an Ion-conducting Plasma Membrane Channel Inhibited by Zinc Ions

2011 ◽  
Vol 286 (14) ◽  
pp. 12221-12233 ◽  
Author(s):  
Sachar Lambert ◽  
Anna Drews ◽  
Oleksandr Rizun ◽  
Thomas F. J. Wagner ◽  
Annette Lis ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Zinc Ions ◽  
Membrane Channel ◽  
Transient Receptor Potential Melastatin ◽  
Ion Conducting ◽  
Transient Receptor

scholarly journals Inhibition of Transient Receptor Potential Melastatin 3 ion channels by G-protein βγ subunits

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Doreen Badheka ◽  
Yevgen Yudin ◽  
Istvan Borbiro ◽  
Cassandra M Hartle ◽  
Aysenur Yazici ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Gabab Receptor ◽  
Receptor Potential ◽  
Heterotrimeric G Proteins ◽  
Drg Neurons ◽  
Signaling Mechanism ◽  
Transient Receptor Potential Melastatin ◽  
Inward Currents ◽  
Mouse Dorsal Root Ganglion ◽  
Transient Receptor

Transient receptor potential melastatin 3 (TRPM3) channels are activated by heat, and chemical ligands such as pregnenolone sulphate (PregS) and CIM0216. Here, we show that activation of receptors coupled to heterotrimeric Gi/o proteins inhibits TRPM3 channels. This inhibition was alleviated by co-expression of proteins that bind the βγ subunits of heterotrimeric G-proteins (Gβγ). Co-expression of Gβγ, but not constitutively active Gαi or Gαo, inhibited TRPM3 currents. TRPM3 co-immunoprecipitated with Gβ, and purified Gβγ proteins applied to excised inside-out patches inhibited TRPM3 currents, indicating a direct effect. Baclofen and somatostatin, agonists of Gi-coupled receptors, inhibited Ca2+ signals induced by PregS and CIM0216 in mouse dorsal root ganglion (DRG) neurons. The GABAB receptor agonist baclofen also inhibited inward currents induced by CIM0216 in DRG neurons, and nocifensive responses elicited by this TRPM3 agonist in mice. Our data uncover a novel signaling mechanism regulating TRPM3 channels.

scholarly journals Sensitivity of TRPM7 channels to Mg2+ characterized in cell-free patches of Jurkat T lymphocytes

2012 ◽  
Vol 302 (11) ◽  
pp. C1642-C1651 ◽  
Author(s):  
Rikki Chokshi ◽  
Masayuki Matsushita ◽  
J. Ashot Kozak
Keyword(s):  
Transient Receptor Potential ◽  
Single Channel ◽  
Receptor Potential ◽  
Whole Cell ◽  
Transient Receptor Potential Melastatin ◽  
Channel Inhibition ◽  
Gradual Development ◽  
Transient Receptor ◽  
Free Membrane ◽  
Inside Out

Transient receptor potential melastatin 7 (TRPM7) channels were originally identified electrophysiologically when depletion of cytosolic Mg2+ resulted in the gradual development of an outwardly rectifying cation current. Conversely, inclusion of millimolar Mg2+ in internal solutions prevented activation of these channels in whole cell patch clamp. We recently demonstrated that the Jurkat T-cell whole cell TRPM7 channels are inhibited by internal Mg2+ in a biphasic manner, displaying high [IC50(1) ≈ 10 μM] and low [IC50(2) ≈ 165 μM] affinity inhibitor sites. In that study, we had characterized the dependence of the maximum cell current density on intracellular Mg2+ concentration. To characterize Mg2+ inhibition in Jurkat T cells in more detail and compare it to whole cell results, we recorded single TRPM7 channels in cell-free membrane patches and investigated the dependence of their activity on Mg2+ added on the cytoplasmic side. We systematically varied free Mg2+ from 265 nM to 407 μM and evaluated the extent of channel inhibition in inside-out patch for 58 patches. We found that the TRPM7 channel shows two conductance levels of 39.0 pS (γ1) and 18.6 pS (γ2) and that both are reversibly inhibited by internal Mg2+. The 39.0-pS conductance is the dominant state of the channel, observed most frequently in this recording configuration. The dose-response relation in inside-out patches shows a steeper Mg2+ dependence than in whole cell, yielding IC50(1) of 25.1 μM and IC50(2) of 91.2 μM.. Single-channel analysis shows that the primary effect of Mg2+ in multichannel patches is a reversible reduction of the number of conducting channels (No). Additionally, at high Mg2+ concentrations, we observed a saturating 20% reduction in unitary conductance (γ1). Thus Mg2+ inhibition in whole cell can be explained by a drop in individual participating channels and a modest reduction in conductance. We also found that TRPM7 channels in some patches were not sensitive to this ion at submaximal Mg2+ concentrations. Interestingly, Mg2+ inhibition showed the property of use dependence: with repeated applications, Mg2+ effect became gradually more potent, which suggests that Mg2+ sensitivity of the channel is a dynamic characteristic that depends on other membrane factors.

Inositol lipids and TRPC channel activation

2007 ◽  
Vol 74 ◽  
pp. 37-45 ◽  
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.

The TRPM7 Channel in the Nervous and Cardiovascular Systems

2020 ◽  
Vol 21 (10) ◽  
pp. 985-992 ◽  
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.

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

2020 ◽  
Vol 17 (3) ◽  
pp. 249-258 ◽  
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.

Characterization of the function of transient receptor potential melastatin 2 in mouse pancreas

Pancreatology ◽  
2019 ◽  
Vol 19 ◽  
pp. S94
Author(s):  
Júlia Fanczal ◽  
Petra Pallagi ◽  
Marietta Görög ◽  
Csaba Péter Bíró ◽  
Tamara Madácsy ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mouse Pancreas ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor
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