Circadian Regulation of Retinoschisin in the Chick Retina

Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843-4458, USA.
Investigative Ophthalmology & Visual Science (Impact Factor: 3.4). 05/2008; 49(4):1615-21. DOI: 10.1167/iovs.07-1189
Source: PubMed


To investigate the circadian regulation and acute illumination effects on the expression and secretion of retinoschisin from vertebrate retinas.
Retinas were studied on the second day of constant darkness (DD) after several days of entrainment to 12-hour light/12-hour dark (LD) cycles in ovo or in vitro. Quantitative real-time PCR and Western immunoblotting were used to examine the mRNA and protein expressions of retinoschisin at different circadian time points. Pharmacologic treatments in whole retina and dissociated retinal cell cultures were used to investigate the cellular mechanisms underlying the circadian regulation of retinoschisin content and secretion. Different illumination conditions were given to examine changes in retinoschisin content in association with acute light/dark adaptation.
The mRNA level, protein expression, and secretion of retinoschisin were under circadian control, all of which were higher at night and lower during the day. The Ras, MAP kinase Erk, CaMKII pathway served as part of the circadian output regulating the rhythmicity of retinoschisin. Blockage of L-type VGCCs dampened the retinoschisin rhythm, but inhibition of L-type VGCCs did not completely abolish the secretion of retinoschisin. The protein expression of retinoschisin also responded to acute illumination changes.
The mRNA and protein expression, as well as retinoschisin secretion, are under circadian control. L-type VGCCs play a role in the circadian regulation of retinoschisin, but the molecular mechanism underlying retinoschisin secretion does not depend on L-type VGCCs. Protein expression of retinoschisin in response to acute illumination changes depends on previous light exposure experience.

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Available from: Liheng Shi, Jun 17, 2014
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    • "Wang et al. [16] described that missense mutations in the signal peptide or discoidin domain lead to intracellular retention of mutant retinoschisins, implicating the corresponding mutated amino acids in the molecular mechanisms underlying retinoschisin secretion. Moreover, it has been reported recently that retinoschisin secretion is under circadian control in chick retina [17]. However, little is known about the intracellular regulatory factors that regulate retinoschisin transit and ultimately its exit from the photoreceptor cells. "
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    ABSTRACT: Retinoschisin is encoded by the gene responsible for X-linked retinoschisis (XLRS), an early onset macular degeneration that results in a splitting of the inner layers of the retina and severe loss in vision. Retinoschisin is predominantly expressed and secreted from photoreceptor cells as a homo-oligomer protein; it then associates with the surface of retinal cells and maintains the retina cellular architecture. Many missense mutations in the XLRS1 gene are known to cause intracellular retention of retinoschisin, indicating that the secretion process of the protein is a critical step for its normal function in the retina. However, the molecular mechanisms underlying retinoschisin's secretion remain to be fully elucidated. In this study, we investigated the role of the F-actin cytoskeleton in the secretion of retinoschisin by treating Weri-Rb1 cells, which are known to secrete retinoschisin, with cytochalasin D, jasplakinolide, Y-27632, and dibutyryl cGMP. Our results show that cytochalasin D and jasplakinolide inhibit retinoschisin secretion, whereas Y-27632 and dibutyryl cGMP enhance secretion causing F-actin alterations. We also demonstrate that high concentrations of taxol, which hyperpolymerizes microtubules, inhibit retinoschisin secretion. Our data suggest that retinoschisin secretion is regulated by the F-actin cytoskeleton, that cGMP or inhibition of ROCK alters F-actin structure enhancing the secretion, and that the microtubule cytoskeleton is also involved in this process.
    Full-text · Article · Jun 2011 · PLoS ONE
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    • "Mutations in the retinoschisin gene (RS1) cause X-linked retinoschisis, a retinal dystrophy that features disorganization of retinal cell layers, disruption of the synaptic structures and neurotransmission between photoreceptors and bipolar cells, and progressive degeneration of rod and cone photoreceptors (Gehrig et al. 1999; Reid et al. 1999; Wang et al. 2002; Tantri et al. 2004; Zeng et al. 2004; Molday et al. 2007). In chicken retinas, mRNA and protein expression of retinoschisin are under circadian control, and inhibition of L-VGCCs with dihydropyridines dampens the circadian rhythm of retinoschisin secretion where only nighttime secretion is affected (Ko et al. 2008). Furthermore, there is a physical interaction between retinoschisin and the L-VGCCα1D subunit (Shi et al. 2009). "
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    ABSTRACT: Ion channels are the gatekeepers to neuronal excitability. Retinal neurons of vertebrates and invertebrates, neurons of the suprachiasmatic nucleus (SCN) of vertebrates, and pinealocytes of non-mammalian vertebrates display daily rhythms in their activities. The interlocking transcription-translation feedback loops with specific post-translational modulations within individual cells form the molecular clock, the basic mechanism that maintains the autonomic approximately 24-h rhythm. The molecular clock regulates downstream output signaling pathways that further modulate activities of various ion channels. Ultimately, it is the circadian regulation of ion channel properties that govern excitability and behavior output of these neurons. In this review, we focus on the recent development of research in circadian neurobiology mainly from 1980 forward. We will emphasize the circadian regulation of various ion channels, including cGMP-gated cation channels, various voltage-gated calcium and potassium channels, Na(+)/K(+)-ATPase, and a long-opening cation channel. The cellular mechanisms underlying the circadian regulation of these ion channels and their functions in various tissues and organisms will also be discussed. Despite the magnitude of chronobiological studies in recent years, the circadian regulation of ion channels still remains largely unexplored. Through more investigation and understanding of the circadian regulation of ion channels, the future development of therapeutic strategies for the treatment of sleep disorders, cardiovascular diseases, and other illnesses linked to circadian misalignment will benefit.
    Full-text · Article · Jul 2009 · Journal of Neurochemistry
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    • "In conclusion, the circadian oscillators in the retina regulate the activity of Akt, and both Ras —PI3K—Akt and Ras—Erk signaling pathways play equally important roles in regulating L- VGCC channel trafficking that leads to the circadian regulation of L-VGCC current amplitudes. The circadian rhythms of L-VGCCs further leads to the circadian control of retinoschisin secretion from photoreceptors that might contribute to the circadian regulation of synaptic plasticity in the retina (Ko et al. 2008). Therefore, the circadian regulation of L- VGCCs is essential to the daily rhythms of retina function and physiology. "
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    ABSTRACT: The daily rhythm of L-type voltage-gated calcium channels (L-VGCCs) is part of the cellular mechanism underlying the circadian regulation of retina physiology and function. However, it is not completely understood how the circadian clock regulates L-VGCC current amplitudes without affecting channel gating properties. The phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling pathway has been implicated in many vital cellular functions especially in trophic factor-induced ion channel trafficking and membrane insertion. Here, we report that PI3K-Akt signaling participates in the circadian phase-dependent modulation of L-VGCCs. We found that there was a circadian regulation of Akt phosphorylation on Thr308 that peaked at night. Inhibition of PI3K or Akt significantly decreased L-VGCC current amplitudes and the expression of membrane-bound L-VGCCalpha1D subunit only at night but not during the subjective day. Photoreceptors transfected with a dominant negative Ras had significantly less expression of phosphorylated Akt and L-VGCCalpha1D subunit compared with non-transfected photoreceptors. Interestingly, both PI3K-Akt and extracellular signal-related kinase were downstream of Ras, and they appeared to be parallel and equally important pathways to regulate L-VGCC rhythms. Inhibition of either pathway abolished the L-VGCC rhythm indicating that there were multiple mechanisms involved in the circadian regulation of L-VGCC rhythms in retina photoreceptors.
    Full-text · Article · Feb 2009 · Journal of Neurochemistry
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