ABSTRACT
Circadian rhythms of physiology and behavior are generated by biological clocks that are synchronized to the cyclic environment by photic or nonphotic cues. The interactions and integration of various entrainment pathways to the clock are poorly understood. Here, we show that the Ras-like G protein Dexras1 is a critical modulator of the responsiveness of the master clock to photic and nonphotic inputs. Genetic deletion of Dexras1 reduces photic entrainment by eliminating a pertussis-sensitive circadian response to NMDA. Mechanistically, Dexras1 couples NMDA and light input to Gi/o and ERK activation. In addition, the mutation greatly potentiates nonphotic responses to neuropeptide Y and unmasks a nonphotic response to arousal. Thus, Dexras1 modulates the responses of the master clock to photic and nonphotic stimuli in opposite directions. These results identify a signaling molecule that serves as a differential modulator of the gated photic and nonphotic input pathways to the circadian timekeeping system.
Subject(s)
Biological Clocks/genetics , Circadian Rhythm/genetics , GTP-Binding Proteins/physiology , Retinal Ganglion Cells/metabolism , Suprachiasmatic Nucleus/metabolism , Visual Pathways/metabolism , ras Proteins/physiology , Animals , Biological Clocks/radiation effects , Circadian Rhythm/radiation effects , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , GTP-Binding Proteins/genetics , Glutamic Acid/metabolism , Light , Light Signal Transduction/drug effects , Light Signal Transduction/genetics , Mice , Mice, Knockout , Mitogen-Activated Protein Kinases/metabolism , Mutation/genetics , Neuropeptide Y/metabolism , Pertussis Toxin/pharmacology , Photic Stimulation , Receptors, N-Methyl-D-Aspartate/metabolism , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/radiation effects , Suprachiasmatic Nucleus/cytology , Suprachiasmatic Nucleus/radiation effects , Synaptic Transmission/drug effects , Synaptic Transmission/genetics , Visual Pathways/cytology , Visual Pathways/radiation effects , ras Proteins/geneticsABSTRACT
Control and treatment of chronic pain remain major clinical challenges. Progress may be facilitated by a greater understanding of the mechanisms underlying pain processing. Here we show that the calcium-sensing protein DREAM is a transcriptional repressor involved in modulating pain. dream(-/-) mice displayed markedly reduced responses in models of acute thermal, mechanical, and visceral pain. dream(-/-) mice also exhibited reduced pain behaviors in models of chronic neuropathic and inflammatory pain. However, dream(-/-) mice showed no major defects in motor function or learning and memory. Mice lacking DREAM had elevated levels of prodynorphin mRNA and dynorphin A peptides in the spinal cord, and the reduction of pain behaviors in dream(-/-) mice was mediated through dynorphin-selective kappa (kappa)-opiate receptors. Thus, DREAM appears to be a critical transcriptional repressor in pain processing.
