melanopsin 332
TRANSCRIPT
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Melanopsin, Pinopsin and Encephalic Photoreception in
BirdsSimon BishopAlice Cowie
Emily PurcellJeannette Shipman
Gemma Sykes
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Outline
• Photoreception in vertebrates
• Importance of the pineal gland and melatonin
• Melanopsin and pinopsin – what are they?
• How melanopsin and pinopsin entrain melatonin production by the pineal gland to light
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Photoreception in Vertebrates• Most vertebrates (birds
included) have both retinal and extra retinal photoreceptors
• These include:– Lateral eyes– Deep brain
photoreceptors– Intracranial pineal organ– Intracranial parapineal
organ (fish only)– Extra-retinal “third eye”
(reptiles and amphibians only)
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Birds and Mammals Compared
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Mammals and Birds compared
• Mammals:– Eyes are the only photoreceptors. – Signals sent from eyes along the retinohypothalamic tract
to the SCN, which acts as a MASTER CLOCK. – SCN sends inhibitory or stimulatory information to the
pineal gland to rhythmically control its production of melatonin.
• Birds:– Much more complex!– Eyes, hypothalamus and pineal gland all act as
photoreceptors AND circadian oscillators.– Melatonin production by the pineal gland can be directly
entrained to the environmental light/dark cycle.
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The Pineal Gland• Particularly important in avian photoreception.• Small endocrine gland in the brain, developmentally
derived from diencephalic tissue.• Primary function to rhythmically synthesize and
release melatonin.
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Melatonin• Indoleamine hormone. • Rhythmically synthesised and
released by cells in the pineal gland.
• Production of melatonin by the pineal gland is stimulated by darkness and inhibited by light.
• Secretion of melatonin peaks in the middle of the night
• Output must be entrained to the light dark cycle.
• Entrainment achieved by photopigments.
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Phototransduction and Entrainment
• Experimental evidence suggests two distinct transduction pathways mediate the effects of light on pineal gland melatonin output:– One causes the acute suppression of
melatonin output– One mediates phase shift entrainment of
the pineal clock
• Each pathway is possibly controlled by a different photopigment.
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What Evidence is there for 2 Phototransduction Pathways?• Experiment 1:
– Deprive cultured pineal cells of Vitamin A– Acute effect of light on melatonin production is
reduced– Phase shifts are unaffected
• Experiment 2:– Apply pertussis toxin to cultured chick pineal cells
(interferes with G proteins which are often coupled with photoreceptors)
– Blocks acute, but not phase-shifting effects of light on melatonin production
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Pinopsin• mRNA rhythmically expressed.• Daily rhythm of expression regulated by light
and an intrapineal circadian oscillator.• Gene expression initially thought to be purely
light-controlled.• However when chickens/isolated pineal glands
were kept in constant darkness rhythmic pinopsin expression continued (albeit at a reduced level).
• Therefore now know that circadian oscillators must also play a role in its control.
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Melanopsin
• Rhythmically expressed (like pinopsin).• In constant darkness, daily amplitudes of
melanopsin gene expression are not reduced, in some cases seem even to increase.
• Therefore seems that regulation of melanopsin production is primarily controlled by the pineal circadian oscillator (unlike pinopsin).
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Daily Cycles in Pinopsin and Melanopsin Levels
• Pinopsin and melanopsin levels low in early morning (ZT 0 – 6).
• Increase in middle of day (ZT 6) by approx. 5-fold.
• Reach a peak between ZT 10 – 12.
• mRNA levels decrease after lights-off.
• Return to low nocturnal levels within 4 – 6 hours.
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Circadian Variations of Melanopsin and Pinopsin mRNA levels in Chick Pineal Glands
under LD 12:12
In vivo In vitro
Holthues H. et al (2004).
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Pinopsin – what is it?• An opsin-like photopigment. • Related to, but distinct from,
other visual opsins.• First isolated from the pineal
gland of the chicken (Gallus domesticus).
• Expressed exclusively in the pineal gland (key difference with melanopsin).
• Precise role still unclear.• Involved in ‘acute
suppression’ pathway???
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Melanopsin – what is it?• Opsin-like photopigment, also
called Opn4, first isolated from photosensitive skin and retinal cells in the African Claw frog (Xenopus laevis).
• In birds, found in:– Specialised photosensitive
ganglion cells in the retina– Iris muscles– Deep brain regions– Pineal gland– Skin cells
• Involved in ‘phase-shift entrainment’ pathway???
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How do they work?• Melanopsin
– Knockout mice have attenuated phase shifting light response
– Transfection makes non-photosensitive cells respond to light
– Linked to Gq-type G-proteins and neuron depolarisation
– But… G-proteins are indiscriminate and use varies between species
• Pinopsin– PTX blocks Gi- and Gt-type
G-proteins, blocking the acute effect of light on pinealocytes in vitro.
– Transducin (Gt1α) is coupled with pinopsin in vivo.
– Pinopsin activated Gt1 in vitro when illuminated
– Therefore pinopsin-Gt1 pathway contributes to the acute pathway
– But… Gq/11α also localises with pinopsin, speculated to be involved with phase-shifting
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In Summary…
• Birds have multiple photoreceptors• Some involved in vision, others in
temporal physiology• Pinopsin and melanopsin – two
photopigments with a role in controlling daily melatonin output by the pineal gland
• Exact functions still unknown but:– Pinopsin – involved in ‘acute effect’…?– Melanopsin – involved in ‘phase-shift
entrainment’ effect…?
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References• Natesan A. et al (2002). Rhythm and Soul in the Avian Pineal. Cell
Tissue Res 309 35 – 45.
• Holthues H. et al (2004). Circadian gene expression patterns of melanopsin and pinopsin in the chick pineal gland. Biochem and Biophys Res Comm 326 160 – 165.
• Oishi T. et al (2001). Multiphotoreceptor and multioscillator system in avian circadian organization Micros Res and Tech 53 43 – 47.
• Peirson S. and Foster R.G. (2006). Melanopsin: Another Way of Signalling Light. Neuron 49 331-339
• Okano T. and Fukada Y. (2001). Photoreception and Circadian Clock System of the Chicken Pineal Gland. Micros Res and Tech 53 72-80
• Wada Y. et al (2000). Phototransduction Molecules in the Pigeon Deep Brain. J. Comp. Neuro. 428 138-144
• Kumar Nayak S. et al (2007). Role of a Novel Photopigment, Melanopsin, in Behavioural Adaptation to Light. Cell. Mol. Life. Sci 64 144-154
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• Bailey M.J. and Cassone V.M. (2005) Melanopsin Expression in the Chick Retina and Pineal Gland Molecular Brain Research 134 345-398
• Foster R.G. and Soni B.G. (1998) Extraretinal Photoreceptors and Their Regulation of Temporal Physiology. Reviews of Reproduction 3 145-150
• Takanaka Y. et al (1998) Light-Dependent Expression of Pinopsin Gene in Chicken Pineal Gland. J. Neurochem. 70 908-913
• Fu Z. et al. (1998) Vitamin A Deficiency Reduces the Responsiveness of Pineal Gland to Light in Japanese Quail (Coturnix japonica) Comp. Biochem. Physiol. 119 593-598