Modulation of nociceptive ion channels by protease-activated receptor-2 in inflammatory pain : molecular mechanisms and therapeutic potential

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Aburamadan, Haneen and Lozon, Yosra and Cyril, Asha Caroline and Parambath, Anagha Nelliyulla and Ali, Najma Mohamed and Jan, Reem Kais and Plevin, Robin and Radhakrishnan, Rajan (2026) Modulation of nociceptive ion channels by protease-activated receptor-2 in inflammatory pain : molecular mechanisms and therapeutic potential. International Journal of Molecular Sciences, 27 (4). 1769. ISSN 1422-0067 (https://doi.org/10.3390/ijms27041769)

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Abstract

Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor (GPCR) expressed in both the peripheral and central nervous systems. It plays a pivotal role in mediating neuroimmune interactions, particularly in the context of inflammation and pain. Upon activation by proteases, PAR2 modulates nociception through signaling cascades that influence key ion channels, including transient receptor potential (TRP) ion channels vanilloid 1 and 4 (TRPV1 and TRPV4), ankyrin 1 (TRPA1), acid-sensing ion channel 3 (ASIC3), P2X purinoceptor 3 (P2X3), Cav3.2 (T-type Ca2+ channel), and potassium Kv7 (M-current) channels, altering their expression and function. Through this crosstalk, PAR2 contributes to heightened neuronal excitability and pain hypersensitivity in various inflammatory conditions. In this narrative review, we highlight and discuss the mechanistic and functional interplay between PAR2 and nociceptive ion channels, which might be contributing to the pathogenesis of inflammatory pain. Targeting these specific molecular interactions between PAR2 and nociceptive ion channels may offer a promising therapeutic strategy for treating inflammatory pain.

ORCID iDs

Aburamadan, Haneen, Lozon, Yosra, Cyril, Asha Caroline, Parambath, Anagha Nelliyulla, Ali, Najma Mohamed, Jan, Reem Kais, Plevin, Robin ORCID logoORCID: https://orcid.org/0000-0002-7849-1220 and Radhakrishnan, Rajan;
CORE (COnnecting REpositories)