time-keeping system: circadian rhythms
TRANSCRIPT
Time-keeping System:
Circadian Rhythms
Helena Illnerová
Institute of Physiology
Academy of Sciences of the Czech Rep.
CIRCADIAN RHYTHMS
sleep-wake cycle
body temperature
behaviour
food and water intake
hormones
metabolism
body fluids
expression of genes
Subjective night
Evening: sleepiness increases
melatonin increases
body temperature decreases
Morning: cortisol increases
melatonin decreases
body temperature increases
The subjective night is not
necessarily equal to the real night
Tau > 24 h: daily phase advance
is necessary
Tau < 24 h : daily phase delay is
necessary
The outside period T = 24 h
Entrainment: Tau* = 24 h
Light Entrainment
• Light in the evening and in the first half of
the night delays phase of the rhythms.
• Light in the second half of the night and in
the morning advances phase of the rhythms
• Light during the subjective day does not
change phase of the rhythms
THE PINEAL GLAND:
SEROTONIN
N-ACETYLSEROTONIN
MELATONIN
N-ACETYLTRANSFERASE
HYDROXYINDOL-O-METHYL
TRANSFERASE
DAY 0 DAY 1
TIME (h)
THE MAMMALIAN CLOCK GENES
Clock
BMal 1 (Mop 3), BMal 2
Per 1, Per 2 (Period)
Cry 1, Cry 2 (Cryptochrome)
Rev – Erb α
CK1 Є CK1 δ (kasein kinase)
CLOCK-CONTROLLED GENES
Per 3
AVP (arginin vasopresin)
Dbp (D-element binding protein)
translation
+ ++ +++
- DNA - - DNA - - DNA –
+ ++ +++
Per mRNA)
protein product of the clock
modification ? transcription
DNA (gene Per)
modified protein
of the clock
Protein transfer to the nucleus
Clock-controlled genes
Overt circadian rhythms
Are the clock genes
responsible for
CHRONOTYPES?
Larks vs. owls?
Vision entrainment
PHOTORECEPTORS retinal rods retinal ganglionic
and cones cells
PHOTOPIGMENT Rodopsin Melanopsin
Optic nerves RHT, GHT
Optic cortex SCN; ?
First, second and third
messengers
GLUTAMATE
cAMP; cGMP; Ca ions; NO
C-FOS; pCREB; PER1; PER2
Hierarchy of the Circadian System
S C N Light
Melatonin
NPY
Glucocorticoids
Restricted feeding
kidney heart pancreas lungs liver
ENTRAINMENT OF THE
TIME-KEEPING SYSTEM
Entainment of the SCN: by light
Entrainment of peripheral
organs:
- From SCN
- By feeding
- Via corticoids
- ?
Peripheral organs as clocks
- Oscillation in the organ culture
- Different periods and phases
- Oscillations persist even after the SCN lesion but become desynchronized
- PERIPHERAL ORGANS ARE CLOCKS PER SE BUT SCN PLAYS THE COORDINATION AND SYNCHRONIZING ROLE
Expression of Genes
About 10% of genes are
expressed in a rhythmic way:
- CLOCK GENES
- CELL CYCLE GENES
- GENES FOR APOPTOSIS
- ORGAN SPECIFIC GENES
Partial hepatectomy
hourglass
Go
G1
S
M
G2
Liver growth
Clocks of
the cell cycle Circadian
clocks
CDC 2
CYCLIN B
CDC 25
WEE 1
BMAL 1
CLOCK
REV-ERBQ
CRY 1, 2
PER 1, 2
TUMOUR GROWTH
• PER2 Bmal1/Clock c Myc
• PER2 p53 apoptosis
• A WEAK CIRCADIAN SYSTEM
METABOLIC DISORDERS-OBESITY
- In food intake (night eating syndrom)
- In balance of rhythms of leptin, ghrelin, insulin (e.g., when sleep is insufficient )
- In loss of appetite (Clock mutant mice)
Disorders of the Circadian
System
Free-run
DSPS
ASPS
Fragmentation of sleep
Higher risk for oncologic diseases
Metabolic disorders
CHRONOBIOLOGY
Molecular Biology
Neurobiology
Ethology
Internal Medicine
Sports and Labour
Medicine
Psychology
Psychiatry
Neurology
Oncology
The wonder of the world,
the beauty and the power,
the shapes of things,
their colour, lights and shades.
These I saw.
Look ye also while life lasts.