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

Liu, Luyu; Yudin, Yevgen; Nagwekar, Janhavi; Kang, Chifei; Shirokova, Natalia; Rohács, Tibor

doi:10.1523/jneurosci.2304-18.2019

Cited by 18 publications

(17 citation statements)

References 43 publications

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“…2020, 21, 4420 2 of 22 function is an attractive first step in the search for future clinical strategies. TRPM8 is diversely regulated in both physiological and pathological conditions by interacting proteins [24,25], splice variants [26], post-translational modifications [27][28][29][30][31], modulatory regions [32] and G protein-coupled receptor signaling cascades [33][34][35][36][37][38]. The latter is particularly relevant during tissue injury and inflammation, where released inflammatory mediators enhance thermal-evoked pain sensation.…”

Section: Introductionmentioning

confidence: 99%

Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons

Rivera

Campos

Orio

et al. 2020

IJMS

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TRPM8 is the main molecular entity responsible for cold sensing. This polymodal ion channel is activated by cold, cooling compounds such as menthol, voltage, and rises in osmolality. In corneal cold thermoreceptor neurons (CTNs), TRPM8 expression determines not only their sensitivity to cold, but also their role as neural detectors of ocular surface wetness. Several reports suggest that Protein Kinase C (PKC) activation impacts on TRPM8 function; however, the molecular bases of this functional modulation are still poorly understood. We explored PKC-dependent regulation of TRPM8 using Phorbol 12-Myristate 13-Acetate to activate this kinase. Consistently, recombinant TRPM8 channels, cultured trigeminal neurons, and free nerve endings of corneal CTNs revealed a robust reduction of TRPM8-dependent responses under PKC activation. In corneal CTNs, PKC activation decreased ongoing activity, a key parameter in the role of TRPM8-expressing neurons as humidity detectors, and also the maximal cold-evoked response, which were validated by mathematical modeling. Biophysical analysis indicated that PKC-dependent downregulation of TRPM8 is mainly due to a decreased maximal conductance value, and complementary noise analysis revealed a reduced number of functional channels at the cell surface, providing important clues to understanding the molecular mechanisms of how PKC activity modulates TRPM8 channels in CTNs.

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Section: Introductionmentioning

confidence: 99%

Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons

Rivera

Campos

Orio

et al. 2020

IJMS

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“…Overall, the contribution of PKC in TRPM8 regulation has remained unclear since the DAG analogue OAG did not inhibit TRPM8 activity [23], and PKC inhibitors failed to block desensitization [23] and menthol-induced currents [24]. Most of the observed effects may likely be attributable to PIP2 hydrolysis, which is required to maintain TRPM8 activity [13]. Our data suggest that activation of PKC, in the presence of MOR expression, prevented channel desensitization.…”

Section: Discussionmentioning

confidence: 77%

“…One major ion channel that transduces cold in sensory DRG neurons is the TRPM8, which is present in peptidergic neurons and can sense temperature changes in the range of innocuous cold (15-28°C) [10][11][12]. TRPM8 is activated by chemical cooling agents such as menthol, but inhibited by inflammatory agents [13,14]. TRPM8 knockout mice show impaired cold sensation, cold allodynia, and analgesia, demonstrating the role of TRPM8 in cold sensation [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Chronic morphine regulates TRPM8 channels via MOR-PKCβ signaling

et al. 2020

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Postoperative shivering and cold hypersensitivity are major side effects of acute and chronic opioid treatments respectively. TRPM8 is a cold and menthol-sensitive channel found in a subset of dorsal root ganglion (DRG) nociceptors. Deletion or inhibition of the TRPM8 channel was found to prevent the cold hyperalgesia induced by chronic administration of morphine. Here, we examined the mechanisms by which morphine was able to promote cold hypersensitivity in DRG neurons and transfected HEK cells. Mice daily injected with morphine for 5 days developed cold hyperalgesia. Treatment with morphine did not alter the expressions of cold sensitive TREK-1, TRAAK and TRPM8 in DRGs. However, TRPM8-expressing DRG neurons isolated from morphine-treated mice exhibited hyperexcitability. Sustained morphine treatment in vitro sensitized TRPM8 responsiveness to cold or menthol and reduced activation-evoked desensitization of the channel. Blocking phospholipase C (PLC) as well as protein kinase C beta (PKCβ), but not protein kinase A (PKA) or Rho-associated protein kinase (ROCK), restored channel desensitization. Identification of two PKC phosphorylation consensus sites, S1040 and S1041, in the TRPM8 and their site-directed mutation were able to prevent the MOR-induced reduction in TRPM8 desensitization. Our results show that activation of MOR by morphine 1) promotes hyperexcitability of TRPM8-expressing neurons and 2) induces a PKCβ-mediated reduction of TRPM8 desensitization. This MOR-PKCβ dependent modulation of TRPM8 may underlie the onset of cold hyperalgesia caused by repeated administration of morphine. Our findings point to TRPM8 channel and PKCβ as important targets for opioid-induced cold hypersensitivity.

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“…Most of the observed effects may likely be attributable to PIP2 hydrolysis, which is required to maintain TRPM8 activity [13].…”

Section: Discussionmentioning

confidence: 99%

Regulation of TRPM8 channels by PKCβ mediates morphine-induced cold hypersensitivity.

Iftinca

Basso

Flynn

et al. 2020

Preprint

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Postoperative shivering and cold hypersensitivity are major side effects of acute and chronic opioid treatments respectively. TRPM8 is a cold and menthol-sensitive channel found in a subset of dorsal root ganglion (DRG) nociceptors. Deletion or inhibition of the TRPM8 channel was found to prevent the cold hyperalgesia induced by chronic administration of morphine. Here, we examined the mechanisms by which morphine was able to promote cold hypersensitivity in DRG neurons and transfected HEK cells. Mice daily injected with morphine for five days developed cold hyperalgesia. Treatment with morphine did not alter the expressions of cold sensitive TREK-1, TRAAK and TRPM8 in DRGs. However, TRPM8-expressing DRG neurons isolated from morphine-treated mice exhibited hyperexcitability. Sustained morphine treatment in vitro sensitized TRPM8 responsiveness to cold or menthol and reduced activation-evoked desensitization of the channel. Blocking phospholipase C (PLC) as well as protein kinase C beta (PKCβ), but not protein kinase A (PKA) or Rho-associated protein kinase (ROCK), restored channel desensitization. Identification of two PKC phosphorylation consensus sites, S1040 and S1041, in the TRPM8 and their site-directed mutation were able to prevent the MOR-induced reduction in TRPM8 desensitization. Our results show that activation of MOR by morphine 1) promotes hyperexcitability of TRPM8-expressing neurons and 2) induces a PKCβ-mediated reduction of TRPM8 desensitization. This MOR-PKCβ dependent modulation of TRPM8 may underlie the onset of cold hyperalgesia caused by repeated administration of morphine. Our findings point to TRPM8 channel and PKCβ as important targets for opioid-induced cold hypersensitivity.

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

Cited by 18 publications

References 43 publications

Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons

Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons

Chronic morphine regulates TRPM8 channels via MOR-PKCβ signaling

Regulation of TRPM8 channels by PKCβ mediates morphine-induced cold hypersensitivity.

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