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Melatonin‐mediated inhibition of Cav3.2 T‐type Ca 2+ channels induces sensory neuronal hypoexcitability through the novel protein kinase C‐eta isoform
Author(s) -
Zhang Yuan,
Ji Heyi,
Wang Jiangong,
Sun Yufang,
Qian Zhiyuan,
Jiang Xinghong,
Snutch Terrance P.,
Sun Yangang,
Tao Jin
Publication year - 2018
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12476
Subject(s) - melatonin , protein kinase c , melatonin receptor , medicine , biology , endocrinology , receptor , microbiology and biotechnology , chemistry , signal transduction
Recent studies implicate melatonin in the antinociceptive activity of sensory neurons. However, the underlying mechanisms are still largely unknown. Here, we identify a critical role of melatonin in functionally regulating Cav3.2 T‐type Ca 2+ channels (T‐type channel) in trigeminal ganglion (TG) neurons. Melatonin inhibited T‐type channels in small TG neurons via the melatonin receptor 2 (MT 2 receptor) and a pertussis toxin‐sensitive G‐protein pathway. Immunoprecipitation analyses revealed that the intracellular subunit of the MT 2 receptor coprecipitated with Gα o . Both shRNA‐mediated knockdown of Gα o and intracellular application of QEHA peptide abolished the inhibitory effects of melatonin. Protein kinase C (PKC) antagonists abolished the melatonin‐induced T‐type channel response, whereas inhibition of conventional PKC isoforms elicited no effect. Furthermore, application of melatonin increased membrane abundance of PKC‐eta (PKC η ) while antagonism of PKC η or shRNA targeting PKC η prevented the melatonin‐mediated effects. In a heterologous expression system, activation of MT 2 receptor strongly inhibited Cav3.2 T‐type channel currents but had no effect on Cav3.1 and Cav3.3 current amplitudes. The selective Cav3.2 response was PKC η dependent and was accompanied by a negative shift in the steady‐state inactivation curve. Furthermore, melatonin decreased the action potential firing rate of small TG neurons and attenuated the mechanical hypersensitivity in a mouse model of complete Freund's adjuvant‐induced inflammatory pain. These actions were inhibited by T‐type channel blockade. Together, our results demonstrated that melatonin inhibits Cav3.2 T‐type channel activity through the MT 2 receptor coupled to novel G βγ ‐mediated PKC η signaling, subsequently decreasing the membrane excitability of TG neurons and pain hypersensitivity in mice.