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Papers of the Week

Papers: 25 May 2019 - 31 May 2019

Animal Studies

2019 Jul 31

J Neurosci



Gαq sensitizes TRPM8 to inhibition by PI(4,5)P depletion upon receptor activation.


Liu L, Yudin Y, Nagwekar J, Kang C, Shirokova N, Rohacs T
J Neurosci. 2019 Jul 31; 39(31):6067-6080.
PMID: 31127000.


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 pro-inflammatory mediators inhibits these channels. It was proposed that this inhibition proceeds via direct binding of G to the channel. TRPM8 requires the plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P or PIP] for activity. It was claimed however 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 reduced inhibition of TRPM8 by activation of G-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 levels in these neurons. PI(4,5)P also reduced inhibition of TRPM8 by activation of heterologously expressed G-coupled muscarinic M1 receptors. Co-expression of a constitutively active G protein that does not couple to PLC inhibited TRPM8 activity, and in cells expressing this protein decreasing PI(4,5)P levels using a voltage sensitive 5'-phosphatase induced a stronger inhibition of TRPM8 activity than in control cells. Our data indicate that upon GPCR activation, G binding reduces the apparent affinity of TRPM8 for PI(4,5)P and thus sensitizes the channel to inhibition induced by decreasing PI(4,5)P levels.Increased sensitivity to heat in inflammation is partially mediated by inhibition of the cold- and menthol sensitive TRPM8 ion channels. Most inflammatory mediators act via GPCR-s that activate the Phospholipase C pathway leading to the hydrolysis of PI(4,5)P How receptor activation by inflammatory mediators leads to TRPM8 inhibition is not well understood. Here we propose that direct binding of G both reduces TRPM8 activity, and sensitizes the channel to inhibition by decreased levels of its cofactor PI(4,5)P Our data demonstrate the convergence of two downstream effectors of receptor activation G and PI(4,5)P hydrolysis in regulation of TRPM8.