Phosphoinositide signaling in somatosensory neurons

Rohács, Tibor

doi:10.1016/j.jbior.2015.11.012

Cited by 19 publications

(12 citation statements)

References 221 publications

(306 reference statements)

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“…Further adding to the complexity of TRPA1 regulation are early signaling events linked to Ca 2+ -dependent phosphoinositide-specific phospholipase C (PLC) enzymes that hydrolyze phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P 2 ; PIP 2 ) in the inner membrane leaflet. [11][12][13]]. Up to date, however, reports are inconsistent regarding the effects of membrane phosphoinositides on TRPA1 [reviewed in refs.…”

Section: Introductionmentioning

confidence: 99%

“…Up to date, however, reports are inconsistent regarding the effects of membrane phosphoinositides on TRPA1 [reviewed in refs. [11][12][13]]. The sites at which these may interact with TRPA1 are not resolved, but most likely involve the membrane proximal regions of the N-and C termini and inter-subunit regions near the inner leaflet of the membrane [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Putative interaction site for membrane phospholipids controls activation of TRPA1 channel at physiological membrane potentials

et al. 2019

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The transient receptor potential ankyrin 1 (TRPA1) channel is a polymodal sensor of environmental irritant compounds, endogenous proalgesic agents, and cold. Upon activation, TRPA1 channels increase cellular calcium levels via direct permeation and trigger signaling pathways that hydrolyze phosphatidylinositol‐4,5‐bisphosphate (PIP2) in the inner membrane leaflet. Our objective was to determine the extent to which a putative PIP2‐interaction site (Y1006‐Q1031) is involved in TRPA1 regulation. The interactions of two specific peptides (L992‐N1008 and T1003‐P1034) with model lipid membranes were characterized by biophysical approaches to obtain information about affinity, peptide secondary structure, and peptide effect in the lipid organization. The results indicate that the two peptides interact with lipid membranes only if PIP2 is present and their affinities depend on the presence of calcium. Using whole‐cell electrophysiology, we demonstrate that mutation at F1020 produced channels with faster activation kinetics and with a rightward shifted voltage‐dependent activation curve by altering the allosteric constant that couples voltage sensing to pore opening. We assert that the presence of PIP2 is essential for the interaction of the two peptide sequences with the lipid membrane. The putative phosphoinositide‐interacting domain comprising the highly conserved F1020 contributes to the stabilization of the TRPA1 channel gate.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Putative interaction site for membrane phospholipids controls activation of TRPA1 channel at physiological membrane potentials

et al. 2019

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“… 12 This results in the formation of the two classical second messengers inositol 1,4,5-trisphopshate, which releases Ca 2+ from intracellular stores, and diacylglycerol, which activates protein kinase C. Activation of G q -coupled receptors by inflammatory mediators, such as bradykinin, or extracellular ATP in DRG neurons plays an important role in inflammatory hypersensitivity. 11 , 13 Downstream targets of the G q pathway include protein kinase C-mediated sensitization of the heat and capsaicin-sensitive Transient Receptor Potential Vanilloid 1 (TRPV1) channels 14 and voltage-gated Na + channels. 15 Activation of G q -coupled receptors may also lead to direct excitation and pain.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory G_i/O-coupled receptors in somatosensory neurons: Potential therapeutic targets for novel analgesics

Yudin

Rohács

2018

Mol Pain

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Primary sensory neurons in the dorsal root ganglia and trigeminal ganglia are responsible for sensing mechanical and thermal stimuli, as well as detecting tissue damage. These neurons express ion channels that respond to thermal, mechanical, or chemical cues, conduct action potentials, and mediate transmitter release. These neurons also express a large number of G-protein coupled receptors, which are major transducers for extracellular signaling molecules, and their activation usually modulates the primary transduction pathways. Receptors that couple to phospholipase C via heterotrimeric Gq/11 proteins and those that activate adenylate cyclase via Gs are considered excitatory; they positively regulate somatosensory transduction and they play roles in inflammatory sensitization and pain, and in some cases also in inducing itch. On the other hand, receptors that couple to Gi/o proteins, such as opioid or GABAB receptors, are generally inhibitory. Their activation counteracts the effect of Gs-stimulation by inhibiting adenylate cyclase, as well as exerts effects on ion channels, usually resulting in decreased excitability. This review will summarize knowledge on Gi-coupled receptors in sensory neurons, focusing on their roles in ion channel regulation and discuss their potential as targets for analgesic and antipruritic medications.

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“…Receptor-induced decrease of PI(4,5)P 2 in the plasma membrane There are conflicting results on whether plasma membrane PI(4,5)P 2 levels decrease in DRG neurons in response to stimulating endogenous G ␣q -coupled bradykinin receptors (Liu et al, 2010;Lukacs et al, 2013b), and there is no information on the effects of other G ␣q -coupled receptors (Rohacs, 2016). Therefore we investigated whether there is a decrease in PI(4,5)P 2 levels in response to the inflammatory cocktail that we used in our electrophysiology experiments.…”

Section: Pi(45)p 2 Alleviates Inhibition Of Trpm8 By Activation Of Gmentioning

confidence: 99%

“…DRG neurons express receptors for various inflammatory mediators, such as bradykinin, ATP, and prostaglandins. Most of those receptors couple to heterotrimeric G-proteins in the G ␣q family and lead to activation of phospholipase C (PLC) (Rohacs, 2016). Activation of these G ␣q -protein-coupled receptors induces thermal hyperalgesia (Caterina et al, 2000) via mechanisms including sensitizing the heat-and capsaicin-activated transient receptor potential vanilloid (TRPV1) channels (Cesare and McNaughton, 1996;Tominagaetal.,2001)andinhibitingthe cold-activated TRPM8 (Premkumar et al, 2005;Zhang et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

G_αq Sensitizes TRPM8 to Inhibition by PI(4,5)P₂ Depletion upon Receptor Activation

et al. 2019

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The cold-and menthol-sensitive transient receptor potential melastatin 8 (TRPM8) channel is important for both physiological temperature detection and cold allodynia. Activation of G-protein-coupled receptors (GPCRs) by proinflammatory mediators inhibits these channels. It was proposed that this inhibition proceeds via direct binding of G ␣q to the channel. TRPM8 requires the plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 or PIP 2 ] for activity. However, it was claimed that a decrease in cellular levels of this lipid upon receptor activation does not contribute to channel inhibition. Here, we show that supplementing the whole-cell patch pipette with PI(4,5)P 2 reduced inhibition of TRPM8 by activation of G ␣q -coupled receptors in mouse dorsal root ganglion (DRG) neurons isolated from both sexes. Stimulating the same receptors activated phospholipase C (PLC) and decreased plasma membrane PI(4,5)P 2 levels in these neurons. PI(4,5)P 2 also reduced inhibition of TRPM8 by activation of heterologously expressed muscarinic M1 receptors. Coexpression of a constitutively active G ␣q protein that does not couple to PLC inhibited TRPM8 activity, and in cells expressing this protein, decreasing PI(4,5)P 2 levels using a voltage-sensitive 5Ј-phosphatase induced a stronger inhibition of TRPM8 activity than in control cells. Our data indicate that, upon GPCR activation, G ␣q binding reduces the apparent affinity of TRPM8 for PI(4,5)P 2 and thus sensitizes the channel to inhibition induced by decreasing PI(4,5)P 2 levels.Increased sensitivity to heat in inflammation is partially mediated by inhibition of the cold-and menthol-sensitive transient receptor potential melastatin 8 (TRPM8) ion channels. Most inflammatory mediators act via G-protein-coupled receptors that activate the phospholipase C pathway, leading to the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ]. How receptor activation by inflammatory mediators leads to TRPM8 inhibition is not well understood. Here, we propose that direct binding of G ␣q both reduces TRPM8 activityandsensitizesthechanneltoinhibitionbydecreasedlevelsofitscofactor,PI(4,5)P 2 .Ourdatademonstratetheconvergenceoftwo downstream effectors of receptor activation, G ␣q and PI(4,5)P 2 hydrolysis, in the regulation of TRPM8.

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Phosphoinositide signaling in somatosensory neurons

Cited by 19 publications

References 221 publications

Putative interaction site for membrane phospholipids controls activation of TRPA1 channel at physiological membrane potentials

Putative interaction site for membrane phospholipids controls activation of TRPA1 channel at physiological membrane potentials

Inhibitory G_i/O-coupled receptors in somatosensory neurons: Potential therapeutic targets for novel analgesics

G_αq Sensitizes TRPM8 to Inhibition by PI(4,5)P₂ Depletion upon Receptor Activation

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Phosphoinositide signaling in somatosensory neurons

Cited by 19 publications

References 221 publications

Putative interaction site for membrane phospholipids controls activation of TRPA1 channel at physiological membrane potentials

Putative interaction site for membrane phospholipids controls activation of TRPA1 channel at physiological membrane potentials

Inhibitory Gi/O-coupled receptors in somatosensory neurons: Potential therapeutic targets for novel analgesics

Gαq Sensitizes TRPM8 to Inhibition by PI(4,5)P2 Depletion upon Receptor Activation

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Inhibitory G_i/O-coupled receptors in somatosensory neurons: Potential therapeutic targets for novel analgesics

G_αq Sensitizes TRPM8 to Inhibition by PI(4,5)P₂ Depletion upon Receptor Activation