Editors' ChoiceCircadian Rhythm

Dexras1 Integrates Photic and Nonphotic Input

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Science's STKE  14 Sep 2004:
Vol. 2004, Issue 250, pp. tw332
DOI: 10.1126/stke.2502004tw332

Many organisms exhibit rhythmic behavior and activity that corresponds to a daily cycle. The circadian clock is influenced by environmental factors that include both light (photic) and nonphotic stimuli (such as food and locomotor activity) (see Van Gelder). Cheng et al. created mice deficient in dexras1, which encodes a guanosine triphosphatase (GTPase) that can also act as a guanine nucleotide exchange factor (GEF) for heterotrimeric G protein α subunits of the Gi/o family. Analysis of the behavior patterns of the mice, along with various ex vivo assays of neurons of the suprachiasmatic nucleus (SCN), indicated that Dexras1 plays a key role in transmitting photic information through activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) type and nonphotic information through the neuropeptide y (NPY) pathway. Phosphorylation of ERK1 and ERK2 (extracellular signal-regulated protein kinases 1 and 2) in response to light entrainment was diminished in dexras1—/—mice. Light activates glutaminergic neurons in the retina, which synapse onto NMDA-expressing neurons of the SCN. NMDA-induced phase shifts in isolated SCN neuron firing were diminished, and in neurons from wild-type animals, these phase shifts were blocked by pharmacologic inhibition of ERK signaling. Pertussis toxin, which blocks Gα signaling, did not affect NMDA-induced phase shifts in either wild-type or dexras1—/— mice. Thus, Dexras1 participates in a G protein-independent signaling pathway, involving NMDA receptor and ERK activation, to allow input from photic signals to the circadian clock. On the nonphotic input side, Dexras1 appears to provide a negative input, such that dexras1—/—mice exhibit altered circadian behavior patterns after nonphotic stimulation that does not cause a similar alteration in circadian patterns in wild-type mice. In slice preparations, SCN neurons from dexras1—/—mice were more responsive to NPY signaling, with NPY inhibiting NMDA-induced phase shifts at lower doses than in wild-type mice. NPY receptors couple to Gi/o proteins, and preparations from the dexras1—/—mice were indistinguishable from wild-type in the effect of NPY on NMDA-induced phase shifts. Thus, Dexras1 appears to provide an inhibitory signal through a Gi/o-dependent mechanism to the NPY pathway for nonphotic signaling to the circadian clock.

R. N. Van Gelder, Resetting the clock: Dexras1 defines a path. Neuron 43, 603-604 (2004). [Online Journal]

H. Y. Cheng, K. Obrietan, S. W. Cain, B. Y. Lee, P. V. Agostino, N. A. Joza, M. E. Harrington, M. R. Ralph, J. M. Penninger, Dexras1 potentiates photic and suppresses nonphotic responses of the circadian clock. Neuron 43, 715-728 (2004). [Online Journal]

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