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. 2024 May;181(9):1438-1451.
doi: 10.1111/bph.16295. Epub 2024 Jan 25.

Inhibition of TRPM8 function by prostacyclin receptor agonists requires coupling to Gq/11 proteins

Cosmin Trif  1 , Alexandra-Maria Banica  1 , Alexandra Manolache  2 , Sorina Andreea Anghel  1 , Debora-Elena Huţanu  2 , Teodora Stratulat  1   2 , Rodica Badea  1 , George Oprita  2 , Tudor Selescu  2 , Stefana M Petrescu  1 , Marco Sisignano  3 , Stefan Offermanns  4 , Alexandru Babes  2 , Sorin Tunaru  1   5
Affiliations
Free article

Inhibition of TRPM8 function by prostacyclin receptor agonists requires coupling to Gq/11 proteins

Cosmin Trif et al. Br J Pharmacol. 2024 May.
Free article

Abstract

Background and purpose: The TRPM8 ion channel is involved in innocuous cold sensing and has a potent anti-inflammatory action. Its activation by lower temperature or chemical agonists such as menthol and icilin induces analgesic effects, reversing hypersensitivity and reducing chronic pain. On the other hand, prostacyclin (PGI2) enhances pain and inflammation by activating the IP receptors. Due to the critical roles of TRPM8 and IP receptors in the regulation of inflammatory pain, and considering their overlapping expression pattern, we analysed the functional interaction between human TRPM8 and IP receptors.

Experimental approach: We transiently expressed human TRPM8 channels and IP receptors in HEK293T cells and carried out intracellular calcium and cAMP measurements. Additionally, we cultured neurons from the dorsal root ganglia (DRGs) of mice and determined the increase in intracellular calcium triggered by the TRPM8 agonist, icilin, in the presence of the IP receptor agonist cicaprost, the IP receptor antagonist Cay10441, and the Gq/11 inhibitor YM254890.

Key results: Activation of IP receptors by selective agonists (cicaprost, beraprost, and iloprost) inhibited TRPM8 channel function, independently of the Gs-cAMP pathway. The potent inhibition of TRPM8 channels by IP receptor agonists involved Gq/11 coupling. These effects were also observed in neurons isolated from murine DRGs.

Conclusions and implications: Our results demonstrate an unusual signalling pathway of IP receptors by coupling to Gq/11 proteins to inhibit TRPM8 channel function. This pathway may contribute to a better understanding of the role of TRPM8 channels and IP receptors in regulating pain and inflammation.

Keywords: TRPM8; inflammatory pain; prostacyclin; prostacyclin receptor.

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