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Summary BBS2051 Biorhythms in Homeostasis Complete Cases
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BBS2051 Biorhythms in Homeostasis Complete Cases yr
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07/04/2020Case 1 – Camping
1. What is the biological clock and where is it located? [thalamus, SCN, muscle, liver, and
other organs]
Circadian Rhythms & The Biological Clock
• Circadian rhythms are endogenous rhythms in physiology or behavior with a cycle length of
approximately 24 hours.
• These rhythms are driven by an intrinsic circadian clock that measures time.
• The “circadian timing system” consists of input pathways that convey information to the circadian
pacemaker, the circadian pacemaker itself, and the mechanism leading to expression of rhythmic
outputs.
• This input mechanism allows the clock to be synchronized or reset by changes in the environment,
and output pathways lead to generation of clear rhythms such as daily changes in locomotor
activity, sleep, and hormone levels.
→Different chronobiological clocks:
• Circadian: occurs every 24 hours
• Utradian: rhythm with a shorter period than 24 hours
• Infradian: rhythm with a longer period than 24 hours
• Diurnal: with an activity during the day, such as humans have
• Nocturnal: with an activity during the night (most rodents)
Location of the biological Clock
• Mammalian cells contain circadian clocks composed of genes that interact in oscillatory
transcriptional networks within cells and regulate the expression of many other genes critical for cell
physiology and metabolism.
• For proper functioning of the circadian timing
system, all the circadian clocks in the body must
be kept synchronized with one another and to
the 24-h day; this is the function of the master
circadian pacemaker, the suprachiasmatic
nucleus (SCN).
→ Extra-Suprachiasmatic Nucleus Brain Clock
• In mammals, the central clock (master circadian
pacemaker) is located in the suprachiasmatic
nucleus (SCN) of the anterior hypothalamus.
• The SCN controls most circadian rhythms in
behavior (e.g., sleep-wake cycle) and physiology
(ex: hormonal rhythms).
• The SCN consists of a heterogeneous population
,07/04/2020
of neuronal and glial cells distributed in two anatomic subdivisions: a ventral “core” region, receiving
retinal input, and a dorsal “shell” region, receiving dense input from the core.
• SCN neurons are special in several important respects:
▪ They receive direct photic input from the retina, which allows them to synchronize to the
day/night cycle.
▪ They have distinct, topographically organized coupling mechanisms, which allow them to
remain synchronized to one another even in constant darkness.
▪ They generate a pronounced circadian rhythm of neuronal firing frequency, which allows
them, through a variety of direct and indirect output pathways, to synchronize other cells
throughout the body.
▪ They are also designed to acts as “team players” within a tissue, depending more on input
from other cells to generate rhythms than fibroblasts do.
• SCN neurons are not always rhythmic: sufficient depolarization, cytoplasmic calcium and cAMP
levels are required to sustain oscillations.
• Overall function of SCN:
a) The SCN master pacemaker synchronizes to the light/dark cycle and in turn synchronizes other
subsidiary cellular oscillators.
b) The SCN also generates a coherent output signal even in the absence of a light/dark cycle,
accounting for the “free-running” circadian (ca. 24 h) rhythms of physiology and behavior that
persist under constant conditions.
→ Clocks in Peripheral Tissues
Most mammalian cell types are capable of circadian oscillation. In normal circumstances, the rhythmicity
in tissues outside the SCN is synchronized by SCN-dependent output signals. These signals include
physiological and behavioral rhythms (ex: body temperature and food intake) and daily fluctuations in
hormone levels (ex: glucocorticoids and melatonin). Thus, rhythms controlled by the SCN synchronize
molecular rhythmicity among cells within a peripheral tissue.
In the absence of rhythmic input from the SCN, oscillators in some tissues become desynchronized, and
thus the organ as a whole loses detectable rhythmicity. Coordination of rhythms within a tissue may
optimize organ-level physiological processes, while a circadian timing system in general may achieve
“internal temporal order” among organs so that organs are prepared to function most efficiently.
• Peripheral cells, such as fibroblasts, hepatocytes, or adipocytes are peripheral cellular clocks.
• Similar to the master clock, cultured fibroblasts are resilient to large changes in temperature and
overall transcription rates.
• In the liver, clock-controlled genes encode key enzymes involved in hepatic metabolism of fatty
acids, cholesterol, bile acids, amino acids, and xenobiotics. The hepatic clock drives a daily rhythm of
glucose export counterbalancing the brain driven, fasting-feeding cycle.
• The adipose tissue also exhibits robust oscillations of core clock components, controlling the
circadian expression of many transcription factors. The adipose tissue secretes several hormones
termed adipokines, including leptin and adiponectin, involved in the regulation of energy balance.
Leptin secretion was shown to be rhythmic.
,07/04/2020
2. Describe how the biological clock works on a molecular level [CLOCK, Bmal, Cry, Per,
etc.] → How can circadian rhythms be 24-hrs?
CLOCK-controlled Genes
Local circadian oscillators regulate gene expression in a tissue specific manner which impact
physiological processes via its output pathways. Rhythmic expression of clock genes requires
sufficient membrane depolarization, cytoplasmic calcium and cAMP & activation of CREB, which can
bind to CRE: Ca2+/cAMP response elements in the DNA, upon phosphorylation. Membrane
depolarization, cytoplasmic calcium and cAMP are cyclic themselves ,they are in as well as output to the
SCN.
→ PER & CRY Regulation [Negative Limb of Feedback Loop]
1) CLOCK and BMAL1 are two transcription
factors. When they form a dimer at E-box
elements, they promote the transcription of
Period (Per 1, Per2, Per3) and Cryptochrome
(Cry1, Cry2) genes.
*In some cell types and neurons, BMAL1 and
NPAS2 form a heterodimer to maintain
rhythmicity because there is no CLOCK.
2) The two transcribed genes form two
proteins: PER and CRY (in the cytoplasm) and
form a dimer. In the cytoplasm, PER and CRY
undergo posttranslational modifications.
3) The nuclear orphan receptors Rev and ROR
control the rhythmic expression of BMAL1,
with peak levels occurring opposite of the peak of PER expression. REV-ERBα acts at ROR and can
thereby inhibit BMAL1 transcription.
Posttranslational Modifications
• Posttranslational modifications, including phosphorylation mediated part by casein Kinases (CKI-
delta, CKI-ε and CKI-I) and GSK-3β, affect the
interactions of PER and Cry proteins.
• AMPK phosphorylates CRY proteins which causes their
proteasomal degradation. Casein kinases
phosphorylate PER proteins and cause their
proteasomal degradation.
• These modifications build a time delay into the
circadian oscillation. This contributes to regulating the
circadian cycle length.
• After delays associated with transcription translation,
dimerization and nuclear entry, the
PER:CRY protein complexes inhibit transcription of
their own genes.
• PER and CRY (protein-protein interactions) form a
, 07/04/2020
complex with casein kinase proteins and can recruit transcriptional repressors.
• Phosphorylation of PER and CRY promotes their protosomal degradation by F-box proteins (FBXL3
and β-TrCP) (mutations lengthens period). This relieves the negative feedback and a new cycle can
begin.
• Protein phosphatase 1 (PP1) dephosphorylates PER and CRY.
• The fine balance between kinases (including CK1 δ/ε and CK2) and phosphatases (protein
phosphatase 1), and subsequent phosphorylation-dependent degradation contribute greatly to
regulating circadian period length. Mutations in these genes can slow or speed up the circadian
cycle.
• Mutations resulting in rapid nuclear accumulation of PER:CRY complexes would lead to a premature
inhibition of transcription. In this case, the clock would either cycle with a very short period or the
system would equilibrate a nonrhythmic steady state.
The high-amplitude rhythm of
PER production controls the
timing of negative feedback.
Collectively, these events lead
to a delayed, negative
feedback to shut off the
transcriptional activation,
resulting in a negative
feedback loop (red arrows).
The positive drive to the
system comes from the
transcription factors CLOCK
and BMAL1. The orphan nuclear receptors RORA (ROR) and REV-ERBα (Rev) control the rhythmic
expression of Bmal1. The antiphase rhythmicity of this second feedback loop is not essential for rhythm
generation, but BMAL1 itself is necessary.
Feedback Loops
In the core feedback loop, proteins like CLOCK and BMAL1
form (hetero)dimers in order to activate the transcription
of their target genes containing E-box elements in the cis-
regulatory regions of their genes. These target genes
include their negative regulators called periods (PER1,
PER2 and PER3) and the Cryptochromes CRY1 and CRY2).
The concentration of BMAL is adjusted by an auxiliary
(=helper-) feedback loop formed by the clock-controlled
nuclear receptors REV-ERBα or RORα.
• Accumulated PER and CRY proteins intensively repress
Ebox-mediated transcription until their levels have
sufficiently decreased.
• RORs: RORα and RORγ are under transcriptional control of CLOCK/BMAL1 heterodimers. RORs
activate RRE-mediated transcription, whereas REV-ERBs strongly suppress it.
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