Melatonin Type 2 Receptor Inhibits Cav3.2 T-type Ca2~+ Channels And The Study On Molecular Mechanism

Objective: To investigate the effects of melatonin type 2(MT2)receptor on Cav3.2 T-type channel currents and clarify the relevant mechanisms in trigeminal ganglion(TG)neurons in mice.Methods: Western blot analysis and immunofluorescence analysis were used to identify the expression and distribution of MT2 receptor in trigeminal ganglia in mice.The whole-cell patch clamp recording was used to investigate the effect of melatonin on Cav3.1,Cav3.2 and Cav3.3 T-type channel currents.Pharmacological approaches were used to clarify its signaling pathways.Behavior tests were used to define the analgesic effects of melatonin in mice.Results: In the present study,we found that: 1)The MT2 receptors were expressed in trigeminal ganglion neurons.2)In a heterologous expression system,activation of MT2 receptor strongly inhibited Cav3.2 T-type channel currents in a dose-dependent manner,but had no effect on Cav3.1 and Cav3.3 current amplitudes.Melatonin at 0.1 ?M reversibly inhibited Cav3.2 T-type channel currents by ~26.94%.3)Application of melatonin increased membrane abundance of PKC-eta(PKC?).4)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.Conclusions: Our results demonstrate that melatonin inhibits Cav3.2 T-type channel activity through the MT2 receptor coupled to the novel PKC? signaling,subsequently decreasing the membrane excitability of TG neurons and pain hypersensitivity in mice.