Nmu/Nms/Gpr176 Triple-Deficient Mice Show Enhanced Light-Resetting of Circadian Locomotor Activity.

The suprachiasmatic nucleus (SCN) is the master circadian clock in mammals and is properly entrained by environmental light cycle. However, the molecular mechanism(s) determining the magnitude of phase shift by light is still not fully understood. The orphan G-protein-coupled receptor Gpr176 is enriched in the SCN, controls the pace (period) of the circadian rhythm in behavior but is not apparently involved in the light entrainment; Gpr176-/- animals display a shortened circadian period in constant darkness but their phase-resetting responses to light are normal. Here, we performed microarray analysis and identified enhanced mRNA expression of neuromedin U (Nmu) and neuromedin S (Nms) in the SCN of Gpr176-/- mice. By generating C57BL/6J-backcrossed Nmu/Nms/Gpr176 triple knockout mice, we noted that the mutant mice had a greater magnitude of phase shift in response to early subjective night light than wildtype mice, while Nmu/Nms double knockout mice as well as Gpr176 knockout mice are normal in the phase shifts induced by light. At the molecular level, Nmu-/-Nms-/-Gpr176-/- mice had a reduced induction of Per1 and cFos mRNA expression in the SCN by light and mildly upregulated circadian expression of Per2, Prok2, Rgs16, and Rasl11b. These expressional changes may underlie the phenotype of the Nmu/Nms/Gpr176 knockout mice. Our data argue that there is a mechanism requiring Nmu, Nms, and Gpr176 for the proper modulation of light-induced phase shift in mice. Simultaneous modulation of Nmu/Nms/Gpr176 may provide a potential target option for modulating the circadian clock.

Gpr19 is a circadian clock-controlled orphan GPCR with a role in modulating free-running period and light resetting capacity of the circadian clock.

Gpr19 encodes an evolutionarily conserved orphan G-protein-coupled receptor (GPCR) with currently no established physiological role in vivo. We characterized Gpr19 expression in the suprachiasmatic nucleus (SCN), the locus of the master circadian clock in the brain, and determined its role in the context of the circadian rhythm regulation. We found that Gpr19 is mainly expressed in the dorsal part of the SCN, with its expression fluctuating in a circadian fashion. A conserved cAMP-responsive element in the Gpr19 promoter was able to produce circadian transcription in the SCN. Gpr19-/- mice exhibited a prolonged circadian period and a delayed initiation of daily locomotor activity. Gpr19 deficiency caused the downregulation of several genes that normally peak during the night, including Bmal1 and Gpr176. In response to light exposure at night, Gpr19-/- mice had a reduced capacity for light-induced phase-delays, but not for phase-advances. This defect was accompanied by reduced response of c-Fos expression in the dorsal region of the SCN, while apparently normal in the ventral area of the SCN, in Gpr19-/- mice. Thus, our data demonstrate that Gpr19 is an SCN-enriched orphan GPCR with a distinct role in circadian regulation and may provide a potential target option for modulating the circadian clock.

Interfacial transmetallation synthesis of a platinadithiolene nanosheet as a potential 2D topological insulator.

The construction of two-dimensional metal complex materials is fascinating because of the structural and functional diversity of these materials. Previously, we have reported the synthesis of electroconductive nickelladithiolene (NiDT) and palladadithiolene (PdDT) nanosheets using benzenehexathiol (BHT). Down the group from Ni, Pd to Pt, there is a distinct positive shift in the reduction potential; as a result, it becomes synthetically more challenging to stabilize Pt2+ than to form metallic Pt(0) in the presence of BHT as a reducing agent. Herein, a novel synthetic strategy for the preparation of platinadithiolene nanosheet (PtDT) using a dibutyltin-protected BHT ligand is reported, leading to transmetallation in the presence of dioxygen. Both free-standing stacked sheets and atomic layer sheets were obtained and characterized by microscopic techniques such as AFM, SEM, and TEM. To study the morphology of the sheets and determine their charge neutrality, X-ray photoelectron (XP) and infrared (IR) spectroscopic techniques were used. Powder X-ray diffraction analysis of the multilayer PtDT indicates a half-way slipped hexagonal configuration in the P3[combining macron]1m space group. The band structure of this PtDT exhibits a band gap at the Fermi level, which is different from that of NiDT in the staggered configuration, and a Dirac gap, indicating the possibility of 2D topological insulation at room temperature. PtDT is insulating but chemically activated by oxidation with I2 to increase the conductivity by more than 106 folds up to 0.39 S cm-1. The MDT sheets exhibit electrocatalytic activity for the hydrogen evolution reaction, and the activity order is NiDT < PdDT < PtDT.