title: Neuromedin U inhibits T-type Ca2+ channel currents and decreases membrane excitability in small dorsal root ganglia neurons in mice.
abstract: Neuromedin U (NMU) has recently been reported to play a role in nociception. However, to date, the relevant mechanisms still remain unknown. In the present study, we investigated the expression profile of NMU receptors in mouse dorsal root ganglia (DRG) and identified a novel functional role of NMU in modulating T-type Ca(2+) channel currents (T-currents) as well as membrane excitability in small DRG neurons. We found that NMU inhibited T-currents in a dose-dependent manner in mouse small DRG neurons that endogenously expressed NMU type 1 (NMUR1), but not NMUR2 receptors. NMU (1μM) reversibly inhibited T-currents by ∼27.4%. This inhibitory effect was blocked by GDP-β-S or pertussis toxin (PTX), indicating the involvement of a G(i/o)α-protein. Using depolarizing prepulse or intracellular application of QEHA, a synthetic peptide which competitively blocks G-protein βγ subunit (G(βγ)) mediated signaling, we found the absence of functional coupling between G(βγ) and T-type Ca(2+) channels. Pretreatment of the cells with H89, a protein kinase A (PKA) inhibitor, or intracellular application of PKI 5-24, blocked NMU-induced T-current inhibition, whereas inhibition of phospholipase C or protein kinase C elicited no such effects. In addition, we observed a significant decreased firing frequency of action potentials of small DRG neurons induced by NMU, which could be abrogated by pretreatment of the cells with NiCl(2) (100 μM). Taken together, these results suggested that NMU inhibits T-currents via PTX-sensitive PKA pathway, which might contribute to its physiological functions including neuronal hypoexcitability in small DRG neurons in mice.
authors.affiliation: Key Laboratory of Pain Research & Therapy, Department of Neurobiology and Medical Psychology, Institute of Neuroscience, Medical College of Soochow University, Suzhou, PR China.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xinghong
authors.initials: X
authors.lastname: Jiang
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Shan
authors.initials: S
authors.lastname: Gong
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Liu
authors.forename: Ligang
authors.initials: L
authors.lastname: Zhou
authors.forename: Jin
authors.initials: J
authors.lastname: Tao
mesh_terms: D000818:Animals; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020747:Calcium Channels, T-Type; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D009479:Neuropeptides; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; C056900:neuromedin U; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases