Background: Phosphatidylinositol 3-Kinases (PI3Ks) are a family of lipid kinases that phosphorylate the D3-hydroxyls of the inositol ring of phosphoinositides, and are responsible for coordinating a diverse range of cellular functions. A canonical pathway of activation of PI3Ks through the interaction of RA-domain with Ras proteins has been well established. In retinal photoreceptors, we have identified a non-canonical pathway of PI3Kγ activation through the interaction of its RA-domain with a putative Ras-like domain (RLD) in alpha subunit of cyclic nucleotide-gated channel (CNGA1) in retinal rod photoreceptors.
Results: The interaction between PI3Kγ and CNGA1 does not appear to play a role in regulation of CNG channel activity, but PI3Kγ uses CNGA1 as an anchoring module to achieve close proximity to its substrate to generate D3-phosphoinositides.
Conclusions: Our studies suggest a functional non-canonical PI3Kγ activation in retinal rod photoreceptor cells.
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http://dx.doi.org/10.1186/s12964-015-0087-9 | DOI Listing |
Hum Mol Genet
January 2025
Department of Ophthalmology, Baylor College of Medicine, 6565 Fannin St, NC205, Houston, TX 77030 United States.
Human diseases with similar phenotypes can be interconnected through shared biological pathways, genes, or molecular mechanisms. Inherited retinal diseases (IRDs) cause photoreceptor dysfunction due to mutations in approximately 300 genes, affecting visual transduction, photoreceptor morphogenesis, and transcription factors, suggesting common pathobiological mechanisms. This study examined the functional relationship between known IRDs genes by integrating binding sites and gene expression data from the key photoreceptor transcription factors (TFs), Crx and Nrl.
View Article and Find Full Text PDFCells
January 2025
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA.
Retinitis pigmentosa (RP) is a hereditary disease characterized by progressive vision loss ultimately leading to blindness. This condition is initiated by mutations in genes expressed in retinal cells, resulting in the degeneration of rod photoreceptors, which is subsequently followed by the loss of cone photoreceptors. Mutations in various genes expressed in the retina are associated with RP.
View Article and Find Full Text PDFJ Physiol
January 2025
Department of Ophthalmology, Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA, USA.
Bipolar cells are vertebrate retinal interneurons conveying signals from rod and cone photoreceptors to amacrine and ganglion cells. Bipolar cells are found in all vertebrates and have many structural and molecular affinities with photoreceptors; they probably appeared very early during vertebrate evolution in conjunction with rod and cone progenitors. There are two types of bipolar cells, responding to central illumination with depolarization (ON) or hyperpolarization (OFF).
View Article and Find Full Text PDFJ Cell Sci
January 2025
Department of Ophthalmology and Visual Sciences, University of New Mexico, Albuquerque, New Mexico 87131, Mexico.
The Rab11-Rabin8-Rab8 ciliogenesis complex regulates the expansion of cilia-derived light-sensing organelles, the rod outer segments, via post-Golgi rhodopsin transport carriers (RTCs). Rabin8, an effector of Rab11 and a nucleotide exchange factor (GEF) for Rab8, is phosphorylated at S272 by NDR2 kinase (aka STK38L), a canine erd gene product linked to the human ciliopathy Leber congenital amaurosis (LCA). Here, we define the step at which NDR2 phosphorylated Rabin8 regulates Rab11-Rab8 succession in X.
View Article and Find Full Text PDFEye (Lond)
January 2025
Division of Experimental Retinal Therapies, Department of Clinical Sciences, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, 19104, USA.
In this review, we summarize the findings of several pre-clinical studies in the canine BEST1 disease model. To this end, client-owned and purpose bred dogs that were compound heterozygotes or homozygotes, respectively, for two or one of 3 different mutations in BEST1 were evaluated by ophthalmic examination, cSLO/sdOCT imaging, and retinal immunohistochemistry to characterize the clinical and microanatomic features of the disease. Subsequently AAV-mediated gene therapy was done to transfer the BEST1 transgene to the RPE under control of a hVMD2 promoter.
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