Intra and Intercellular Modulation of Circadian Entrainment in the Scn: The Role of Nitric Oxide

*Corresponding author e-mail: jjosechiesa@unq.edu.ar The synchronization to light-dark (LD) cycles of the circadian clock is determined by differential phase-shifting established by the own clock phase (i.e., entrainment), which is predicted by phase-response curve (PRC). Photic Glutamate/Ca2+ activation of neuronal nitric oxide synthase (nNOs) through phosphorylation by its Calcium-dependent kinase II (CAMkII), leads to the increase of nitric oxide (NO) levels. Intracellular NO levels enhance a GC-cGMP-dependent kinase (PKG) activity, specifically during the late subjective night for light-induced phase advances. Also using Glutamate/Ca2+, a bifurcation in this signal transduction pathway is neccesary for photic-induced delays through NO-dependent activation of Ca2+ ryanodine channels. Both mechanisms converge to the phosphorylation of the transcription factor Ca2+/cAMP-responsive element binding protein (CREB), which activates Perl and Per2 genes in the SCN for clock phase-resetting. At the intracellular level, the availability of both pathways leading to opposite phase-shifts, is an output which depends on the own clock phase. Besides its established role as an intracellular messenger, NO is also a component of the intercellular SCN communication. Extracellular NO is necessary for the photic signal spread into the SCN for the light-pulseinduced advances, but it is not involved for delays. In addition, extracellular NO communication is involved in the entrainment by advances to skelleton photoperiod cycles shorter than 24 hs (T23 cycles), but not in the entrainment by delays to T25 cycles. As well as blocking this non-parametric entrainment to T23 cycles, the extracellular-NO scavenging also inhibits the light-induced Perl gene activation. These results indicate a direct linkage between extracellular NO signaling and the molecular phase-resetting of the circadian clock. Thus, circadian entrainment depends on the intercellular NO communication of the light messenge within the SCN tissue. Publication History Article published online: 16 June 2026 © 2009. Brazilian Sleep Academy. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Thieme Revinter Publicações Ltda. Rua Rego Freitas, 175, loja 1, República, São Paulo, SP, CEP 01220-010, Brazil