Light-Driven Calcium Signals in Mouse Cone Photoreceptors

Wei, Tao; Schubert, Timm; Paquet-Durand, François; Tanimoto, Naoyuki; Chang, Le; Koeppen, Katja; Ott, Thomas; Griesbeck, Oliver; Seeliger, Mathias W.; Euler, Thomas; Wissinger, Bernd

doi:10.1523/jneurosci.6432-11.2012

Cited by 41 publications

(86 citation statements)

References 76 publications

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“…2012). However, in photoreceptors neither NOS nor sGC29 are expressed so that this pathway to raise cGMP is unavailable. Instead in photoreceptors, PARP activity and cGMP-signaling may be connected in at least two possible ways: (1) via PARP-dependent regulation of gene expression30, which could have a bearing on GC or on GC regulating enzymes31.…”

Section: Discussionmentioning

confidence: 99%

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Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration

Sahaboglu

Barth

Secer

et al. 2016

Sci Rep

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The enzyme poly-ADP-ribose-polymerase (PARP) mediates DNA-repair and rearrangements of the nuclear chromatin. Generally, PARP activity is thought to promote cell survival and in recent years a number of PARP inhibitors have been clinically developed for cancer treatment. Paradoxically, PARP activity is also connected to many diseases including the untreatable blinding disease Retinitis Pigmentosa (RP), where PARP activity appears to drive the pathogenesis of photoreceptor loss. We tested the efficacy of three different PARP inhibitors to prevent photoreceptor loss in the rd1 mouse model for RP. In retinal explant cultures in vitro, olaparib had strong and long-lasting photoreceptor neuroprotective capacities. We demonstrated target engagement by showing that olaparib reduced photoreceptor accumulation of poly-ADP-ribosylated proteins. Remarkably, olaparib also reduced accumulation of cyclic-guanosine-monophosphate (cGMP), a characteristic marker for photoreceptor degeneration. Moreover, intravitreal injection of olaparib in rd1 animals diminished PARP activity and increased photoreceptor survival, confirming in vivo neuroprotection. This study affirms the role of PARP in inherited retinal degeneration and for the first time shows that a clinically approved PARP inhibitor can prevent photoreceptor degeneration in an RP model. The wealth of human clinical data available for olaparib highlights its strong potential for a rapid clinical translation into a novel RP treatment.

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Section: Discussionmentioning

confidence: 99%

“…For cone examination in long-term experiments, HR2.1:TN-XL x rd1 (rd1 TN-XL ) animals were used that stably express the TN-XL biosensor in cones29. Animals were housed under standard white cyclic lighting, had free access to food and water, and were used irrespective of gender.…”

Section: Methodsmentioning

confidence: 99%

Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration

Sahaboglu

Barth

Secer

et al. 2016

Sci Rep

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“…Activity-dependent Ca 2+ influx into the synapse accounts for a very large proportion of the photoreceptor calcium currents [19], thus Ca V 1.4(α 1F ) is a crucial provider of Ca 2+ in photoreceptors. In addition to its role in synaptic transmission, Ca 2+ also acts as an intracellular second messenger and plays important roles both in adulthood and during development.…”

Section: Introductionmentioning

confidence: 99%

Calcium Channel-Dependent Molecular Maturation of Photoreceptor Synapses

Zabouri

Haverkamp

2013

PLoS ONE

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Several studies have shown the importance of calcium channels in the development and/or maturation of synapses. The CaV1.4(α1F) knockout mouse is a unique model to study the role of calcium channels in photoreceptor synapse formation. It features abnormal ribbon synapses and aberrant cone morphology. We investigated the expression and targeting of several key elements of ribbon synapses and analyzed the cone morphology in the CaV1.4(α1F) knockout retina. Our data demonstrate that most abnormalities occur after eye opening. Indeed, scaffolding proteins such as Bassoon and RIM2 are properly targeted at first, but their expression and localization are not maintained in adulthood. This indicates that either calcium or the CaV1.4 channel, or both are necessary for the maintenance of their normal expression and distribution in photoreceptors. Other proteins, such as Veli3 and PSD-95, also display abnormal expression in rods prior to eye opening. Conversely, vesicle related proteins appear normal. Our data demonstrate that the CaV1.4 channel is important for maintaining scaffolding proteins in the ribbon synapse but less vital for proteins related to vesicular release. This study also confirms that in adult retinae, cones show developmental features such as sprouting and synaptogenesis. Overall we present evidence that in the absence of the CaV1.4 channel, photoreceptor synapses remain immature and are unable to stabilize.

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“…In the retinal photoreceptors, energy consumption is highly compartmentalized (Linton et al 2010, Wei et al 2012). There is heavy energy expenditure in the outer segments of photoreceptors where phototransduction and protein transport for outer segment renewal are taking place in response to various light intensities (Korenbrot 1995, Koutalos & Yau 1996).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, because the retinal light sensitivities are under circadian regulation (Cameron and Lucas, 2009; Lu et al, 1995; Manglapus et al, 1998; McGoogan and Cassone, 1999), and the retinal energy consumption is light-dependent (Linton et al 2010, Wei et al 2012), we hypothesized that the overall retinal energy expenditure and production could be under circadian control. In this report, we examined the possibility of AMPK serving in the circadian regulation of L-VGCCs in the retina, which might shed light on the role of AMPK in modulating retinal light sensitivities.…”

Section: Introductionmentioning

confidence: 99%

A new role for AMP‐activated protein kinase in the circadian regulation of L‐type voltage‐gated calcium channels in late‐stage embryonic retinal photoreceptors

Huang

Shi

Lin

et al. 2015

Journal of Neurochemistry

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AMPK is a cellular energy sensor, which is activated when the intracellular ATP production decreases. The activities of AMPK display circadian rhythms in various organs and tissues, indicating that AMPK is involved in the circadian regulation of cellular metabolism. In vertebrate retina, the circadian clocks regulate many aspects of retinal function and physiology, including light/dark adaption, but whether and how AMPK was involved in the retinal circadian rhythm was not known. We hypothesized that the activation of AMPK (measured as phosphorylated AMPK) in the retina was under circadian control, and AMPK might interact with other intracellular signaling molecules to regulate photoreceptor physiology. We combined ATP assays, Western blots, immunostaining, patch-clamp recordings, and pharmacological treatments to decipher the role of AMPK in the circadian regulation of photoreceptor physiology. We found that the overall retinal ATP content displayed a diurnal rhythm that peaked at early night, which was nearly anti-phase to the diurnal and circadian rhythms of AMPK phosphorylation. AMPK was also involved in the circadian phase-dependent regulation of photoreceptor L-type voltage-gated calcium channels (L-VGCCs), the ion channel essential for sustained neurotransmitter release. The activation of AMPK dampened the L-VGCC currents at night with a corresponding decrease in protein expression of the L-VGCCα1 pore-forming subunit, while inhibition of AMPK increased the L-VGCC current during the day. AMPK appeared to be upstream of extracellular-signal-regulated kinase (ERK) and mammalian/mechanistic target of rapamycin complex 1 (mTORC1) but downstream of adenylyl cyclase in regulating the circadian rhythm of L-VGCCs. Hence, as a cellular energy sensor, AMPK integrates into the cell signaling network to regulate the circadian rhythm of photoreceptor physiology. We found that in chicken embryonic retina, the activation of AMP-Activated Protein Kinase (AMPK) is under circadian control and anti-phase to the retinal ATP rhythm. While ATP content is higher at night, phosphorylated AMPK (pAMPK) is higher during the day. AMPK appears to be upstream of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and mammalian target of rapamycin complex 1 (mTORC1) but downstream of adenylyl cyclase in regulating the circadian rhythm of L-VGCCs. Therefore, as a cellular energy sensor, AMPK integrates into the cell signaling network to regulate the circadian rhythm of photoreceptor physiology.

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Light-Driven Calcium Signals in Mouse Cone Photoreceptors

Abstract: Calcium mediates various neuronal functions. The complexity of neuronal

Cited by 41 publications

References 76 publications

Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration

Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration

Calcium Channel-Dependent Molecular Maturation of Photoreceptor Synapses

A new role for AMP‐activated protein kinase in the circadian regulation of L‐type voltage‐gated calcium channels in late‐stage embryonic retinal photoreceptors

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