Editing CREB (section)

== Involvement in circadian rhythms ==
[[Entrainment (chronobiology)|Entrainment]] of the mammalian circadian clock is established via light induction of [[Period (gene)|PER]]. Light excites [[melanopsin]]-containing [[Intrinsically photosensitive retinal ganglion cells|photosensitive retinal ganglion cells]] which signal to the [[suprachiasmatic nucleus]] (SCN) via the [[retinohypothalamic tract]] (RHT). Excitation of the RHT signals the release of glutamate which is received by [[NMDA receptor]]s on SCN, resulting in a calcium influx into the SCN. Calcium induces the activity of Ca<sup>2+</sup>/[[CAMK|calmodulin-dependent protein kinases]], resulting in the activation of [[Protein kinase A|PKA]], [[Protein kinase C|PKC]], and [[Casein kinase 2|CK2]].<ref>{{Cite journal|title = Circadian gating of neuronal functionality: a basis for iterative metaplasticity|last1 = Iyer|first1 = Rajashekar|date = September 19, 2014|journal = Frontiers in Systems Neuroscience|doi = 10.3389/fnsys.2014.00164|pmid = 25285070|last2 = Wang|first2 = Tongfei|last3 = Gillette|first3 = Martha|author-link3=Martha Gillette|pmc=4168688|volume=8|pages=164|doi-access = free}}</ref> These kinases then phosphorylate CREB in a circadian manner that further regulates downstream gene expression.<ref>{{Cite journal |last1=Obrietan |first1=Karl |last2=Impey |first2=Soren |last3=Smith |first3=Dave |last4=Athos |first4=Jaime |last5=Storm |first5=Derrick R. |date=April 11, 2002 |title=Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. |journal= Journal of Biological Chemistry|volume=274 |issue=25 |pages=17748–17756 |doi=10.1074/jbc.274.25.17748 |pmid=10364217|doi-access=free }}<!--|access-date = April 21, 2015--></ref> The phosphorylated CREB recognizes the cAMP Response Element and serves as a transcription factor for [[PER1|Per1]] and [[PER2|Per2]], two genes that regulate the mammalian circadian clock. This induction of PER protein can entrain the circadian clock to light/dark cycles inhibits its own transcription via a transcription-translation feedback loop which can advance or delay the circadian clock. However, the responsiveness of PER1 and PER2 protein induction is only significant during the subjective night.<ref name=":0" />

=== Discovery of CREB involvement in circadian rhythms ===
[[Michael E. Greenberg|Michael Greenberg]] first demonstrated the role of CREB in the mammalian circadian clock in 1993 through a series of experiments that correlated phase-specific light pulses with CREB phosphorylation. In vitro, light during the subjective night increased phosphorylation of CREB rather than CREB protein levels. In vivo, phase shift-inducing light pulses during the subjective night correlated with CREB phosphorylation in the SCN.<ref>{{Cite journal|title = Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock|journal = Science|date = April 9, 1993|issn = 0036-8075|pmid = 8097062|pages = 238–241|volume = 260|issue = 5105|doi = 10.1126/science.8097062|first1 = D. D.|last1 = Ginty|first2 = J. M.|last2 = Kornhauser|first3 = M. A.|last3 = Thompson|first4 = H.|last4 = Bading|first5 = K. E.|last5 = Mayo|first6 = J. S.|last6 = Takahashi|first7 = M. E.|last7 = Greenberg|bibcode = 1993Sci...260..238G}}</ref> Experiments by Gunther Schutz in 2002 demonstrated that mutant mice lacking the Ser142 phosphorylation site failed to induce the clock regulatory gene mPer1 in response to a light pulse. Furthermore, these mutant mice had difficulty entraining to light-dark cycles.<ref>{{Cite journal|last1=Gau|first1=Daniel|last2=Lemberger|first2=Thomas|last3=von Gall|first3=Charlotte|last4=Kretz|first4=Oliver|last5=Le Minh|first5=Nguyet|last6=Gass|first6=Peter|last7=Schmid|first7=Wolfgang|last8=Schibler|first8=Ueli|last9=Korf|first9=Horst W.|date=April 11, 2002|title=Phosphorylation of CREB Ser142 Regulates Light-Induced Phase Shifts of the Circadian Clock|journal=Neuron|volume=34|issue=2|pages=245–253|doi=10.1016/S0896-6273(02)00656-6|pmid=11970866|s2cid=14507897|doi-access=free}}<!--|access-date = April 21, 2015--></ref>