Section 1.4.pdf

Section 1 Hormones Receptors and Rhythms Part 4 Mimosa Pudica – Leaf movement plant that if you touch it: will shrink during night, leaves close up When he kept the plants in the dark: plant continued to open up and close in a 24h period (cyclicality will shorten eventually if he continues the exper...

Section 1 Hormones Receptors and Rhythms Part 4 Mimosa Pudica – Leaf movement plant that if you touch it: will shrink during night, leaves close up When he kept the plants in the dark: plant continued to open up and close in a 24h period (cyclicality will shorten eventually if he continues the experiment for a long time) Jean-Jacques Mairan 18th century Chronobiologist biology of clock/time Rhythms v Endogenous mechanisms: Signal from the brain independent of external cues v Mechanisms entrained by external cues (light-dark cycle; temperature; feeding; social cues; stress) synchronization v 24-hour cycle: circadian rhythm (hormone secretion; sleep-wake; body temperature) v Longer cycle: infradian rhythm (reproductive cycle; hibernation; molting; breeding) REM = 40 minutes v Shorter cycle: ultradian rhythm (sleep stages; heartbeat; hormone secretion) respiratory rate Endocrine rhythms v Examples of circadian rhythms: – Cortisol secretion: maximal between 6-8 a.m. prolactine – GH, PRL maximal secretion 1h after going to sleep v Rhythms may change during development – Gonadotrophin: Released mainly at night during puberty. Released in a pulsatile fashion in adults. v Rhythms must be considered when measuring hormone levels peaks at night time molecular clock Core clock in mammals 2 proteins at the center of the molecular clock: CLOCK AND BMAL —> TF, function together as a heterodimer —> bind to DNA sequence (promoter) E-box —> transcriptional activators —> drives expression of CCGs NR (nuclear receptor): ROR and Rev ROR = transcriptional activator REV = transcriptional repressor of BMAL Amount of BMAL depends on ROR and Rev and balance Turn on/turn off system: 1st set of protein = CRY genes 2nd set = PER genes function as heterodimers = inhibition of gene expression activity, physically interact with CLOCK and BMAL and inhibit their gene activation function CRY and PER = CCGs Negative feedback loop Level of CRY and PER increase, eventually CLOCK and BMAL stop functioning and CRY and PER level goes down = up and down regulation based on transcription CCGs = Circadian-clock controlled genes Rev-Erb a/b = NR1D1 and NR1D2 - Orphan Receptors ROR a/b = Retinoic-acid-receptor-related Orphan Receptor NR1F1, NR1F2, NR1F3 suprachiasmatic nucleus SCN is the circadian pacemaker neurons interrelated so all fire together v Suprachiasmatic nucleus neurons and astrocytes fire with circadian rhythm v Intrinsic rhythm of approx. 24h 11 min v Light is the main Zeitgeber that entrains If no external cues: goes off phase SCN clock Neurons have intrinsic rhytmicity: light synchronizes them v Photosensitive ganglion cells are primary responsible for entrainment Ganglion cells Light comes from our eyes (ganglion cells in retina that are sensible to light) that can reset our molecular clock Ganglion cells = most important for SCN rhythmicity Peripheral Clocks clock functions intrinsic to peripheral tissues (ex: liver, but doesn’t have photoreceptor, regulated from SCN) Feeding can reset the liver clock in addition by SCN Exercise can regulate muscle clock too vRetinohypthalamic tract – neuronal connection from the retina to SCN Pineal gland acts as link between external photoperiod and internal milieu GPCR NAT = N-acetyl transferase vSCN regulates melatonin production in pineal gland by pinealocytes vSCN has melatonin Receptors – light and melatonin can reset the clock Melatonin is the major hormone secreted by the pineal gland rodents: nocturnal animals and during daytime, they sleep Melatonin high during night time even in rodents Over time: melatonin up and down, regular interval depending on day and night circadian rhythm of melatonin release (Synthesized from tryptophan) interval between 2 melatonin peak smaller during winter and longer during summer Pineal Gland involved in control of Circadian Rhythms all endocrine functions go down as we age vSecretes melatonin (hormone of the dark) v10-fold increase in the dark depending on age vNeural connection with SCN through MT1 receptor vNeural connection with MT2 receptors in the retina vMT1/2 receptors present in other tissues vMelatonin regulates production of Cortisol, GnRH, Gonadotropins, TSH Endocrine rhythms -- subjects without sleep -- subjects with sleep sleeping is important https://doi.org/10.1677/JOE-07-0378 Other functions of Melatonin vAdjustment of jet-lag (esp. if travelling east > 5 time zones) vSleeping aid in elderly (4 min decrease in time to fall asleep, 12 min increase in total sleep) vMarketed as “Health Food Additive” very high doses vAntioxidant (anti-aging properties?); but supraphysiological not really conclusive levels vEnhancement of immunity; Tumor therapy; evidence is not clear vAdverse side effects: v Daytime sleepiness and hypothermia v Desensitization of melatonin receptors if doses too high v Possible adverse events in those with seizures v Possible interaction with those taking coumadin/warfarin anticoagulant Usually feedback Control of synthesis and secretion General + and – feedback systems Hierarchical multi-tier regulation Endocrine disorders v Overproduction v Underproduction v Altered tissue response diabetes v Tumors of endocrine organ v Excessive hormone metabolism