Neuromedin S

NMS activates NMUR1 and NMUR2 receptors with potency comparable to NMU, coupling through Gq to activate PLC, IP3, and intracellular calcium. In the SCN, NMS-expressing neurons project widely within the SCN and to downstream brain regions, synchronizing circadian rhythms. NMUR2 in the hypothalamus mediates the anorexigenic and HPA-activating effects that NMS shares with NMU.

NMS is highly co-expressed with vasoactive intestinal peptide (VIP) and gastrin-releasing peptide (GRP) in SCN neurons. NMS acts as a SCN neurotransmitter, synchronizing the firing patterns of SCN cells and regulating Per1 and Per2 clock gene expression. NMS-specific knockdown in the SCN disrupts circadian locomotor rhythms in mice, demonstrating a non-redundant role in the SCN clockwork beyond what VIP alone provides.

NMS injected into the SCN phase-shifts circadian locomotor rhythms in a manner dependent on the circadian phase of administration, consistent with a clock-resetting function. NMS-Cre mouse models with specific SCN NMS neuron manipulation reveal these cells as critical pacemakers for both behavioral and molecular circadian rhythms.

ICV NMS administration reduces food intake in mice with potency similar to NMU. The anorexigenic effect depends on intact NMUR2 signaling in the hypothalamus. NMS may coordinate energy balance with the time-of-day through its dual role in the SCN and feeding circuits, ensuring feeding behavior aligns with the active phase.

NMS activates CRH release from the PVN and stimulates HPA axis responses, linking circadian timing with stress reactivity. NMS also regulates LH pulsatility through hypothalamic NMUR2, connecting reproductive cyclicity to the circadian system. These roles suggest NMS integrates clock function with energy, stress, and reproductive systems.