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Zhang, Y.* ; Qian, Z.* ; Jiang, D. ; Sun, Y.* ; Gao, S.* ; Jiang, X.* ; Wang, H.* ; Tao, J.*

Neuromedin B receptor stimulation of Cav3.2 T-type Ca2+ channels in primary sensory neurons mediates peripheral pain hypersensitivity.

Theranostics 11, 9342-9357 (2021)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
Background: Neuromedin B (Nmb) is implicated in the regulation of nociception of sensory neurons. However, the underlying cellular and molecular mechanisms remain unknown. Methods: Using patch clamp recording, western blot analysis, immunofluorescent labelling, enzyme-linked immunosorbent assays, adenovirus-mediated shRNA knockdown and animal behaviour tests, we studied the effects of Nmb on the sensory neuronal excitability and peripheral pain sensitivity mediated by Cav3.2 T-type channels. Results: Nmb reversibly and concentration-dependently increased T-type channel currents (IT) in small-sized trigeminal ganglion (TG) neurons through the activation of neuromedin B receptor (NmbR). This NmbR-mediated IT response was Gq protein-coupled, but independent of protein kinase C activity. Either intracellular application of the QEHA peptide or shRNA-mediated knockdown of Gβ abolished the NmbR-induced IT response. Inhibition of protein kinase A (PKA) or AMP-activated protein kinase (AMPK) completely abolished the Nmb-induced IT response. Analysis of phospho-AMPK (p-AMPK) revealed that Nmb significantly activated AMPK, while AMPK inhibition prevented the Nmb-induced increase in PKA activity. In a heterologous expression system, activation of NmbR significantly enhanced the Cav3.2 channel currents, while the Cav3.1 and Cav3.3 channel currents remained unaffected. Nmb induced TG neuronal hyperexcitability and concomitantly induced mechanical and thermal hypersensitivity, both of which were attenuated by T-type channel blockade. Moreover, blockade of NmbR signalling prevented mechanical hypersensitivity in a mouse model of complete Freund's adjuvant-induced inflammatory pain, and this effect was attenuated by siRNA knockdown of Cav3.2. Conclusions: Our study reveals a novel mechanism by which NmbR stimulates Cav3.2 channels through a Gβγ-dependent AMPK/PKA pathway. In mouse models, this mechanism appears to drive the hyperexcitability of TG neurons and induce pain hypersensitivity.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Neuromedin B Receptor ; Protein Kinase A ; T-type Ca2+ Channel ; Trigeminal Ganglion Neurons; Protein-kinase-c; Gated Calcium-channels; Beta-gamma-subunits; Corticotropin-releasing-factor; Trigeminal Ganglion; Neuropathic Pain; International-union; Cardiac-hypertrophy; Glomerulosa Cells; Modulation
e-ISSN 1838-7640
Zeitschrift Theranostics
Quellenangaben Band: 11, Heft: 19, Seiten: 9342-9357 Artikelnummer: , Supplement: ,
Verlag Ivyspring
Verlagsort Po Box 4546, Lake Haven, Nsw 2263, Australia
Begutachtungsstatus Peer reviewed
Förderungen Priority Academic Program Development of Jiangsu Higher Education Institutions
Natural Science Foundation of Colleges and Universities in Jiangsu Province
Natural Science Foundation of Jiangsu Province
Science and Technology Bureau of Suzhou
Jiangsu Key Laboratory of Neuropsychiatric Diseases
Discipline Leader Program of Pudong New Area Health Committee
Science and Technology Plan of Jiangxi Health Committee
Guiding Science and Technology Projects of Ji'an City
National Natural Science Foundation of China