OrganismsfromfliestohumanshavedailycircADIanrhythmsentrainedwiththe24-hourcycleofdayandnightthatregulatemanyphysiologicalsystems.Inmammals,thereappearstobeamasterregulatorofcircadianrhythmsinthehypothalamus,aswellasadditionalperipheralmechanisms.Thebasicframeworkofthemolecularpathwaysinthecellthatproduceandmaintainthesedailyrhythmshasbeenelucidated.Thecentralfeatureofthecircadianpathwaysaretwotranscriptionfactors,BMAl1andClock,thatareexpressedina24hourcycleandthatacttogetherasaheterodimertoregulatetheexpressionofothergenesinvolvedinmaintainingthecircadianrhythm.Bmal1andClockactivatetranscriptionofmultiplePeriod(per)andCryptochrome(Cry)genes.WhentheactivityofBmal1andClockismaximal,PerandCrygenesaretranscribed,andthentranslatedinthecytoplasm.ThetranslatedPerandCrygenesformacomplexinthecytoplasmthatistransportedbackintothenucleus.Inthenucleus,PerandCryformafeedbackloopthatinhibitstranscriptionalactivationbyBmal1andClock,loweringtheirownexpressionintheprocess.Atthesametime,PerandCryincreasetranscriptionofBmal1andClockgenes,toinitiatethenextphaseofthecycleonceagain.Thiscyclerunsautonomouslyinthecell,causingjetlagduringtravel,butcanberegulatedtoretraintochangesinthelightcycle.Factorsthatregulatethecycleincludecaseinkinase1epsilon(CK1e)thatphosphorylatesPer2andinducesitsdegradation.MutationofPER2inhumanshasbeengeneticallylinkedtochangesinhumansleeppatterns.Furtherexplorationofthefactorsthatregulatecircadianrhythmsmayenablemanipulationofthesysteminsleepdisorders.

Contributor:GlennCroston,PhD

REFERENCES:RussoE.CircadianRhythmHomologyandDivergence.TheScientist2000July:pp14-16Shearmanetal.Science.2000May12;288(5468):1013-9.Interactingmolecularloopsinthemammaliancircadianclock.Toh,KLetal.Science.2001Feb9;291(5506):1040-3.AnhPer2phosphorylationsitemutationinfamilialadvancedsleepphasesyndrome.

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