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The N-Formylpeptide Chemotactic Receptor
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Studies with the prototype G protein-coupled receptors rhodopsin and the β2 adrenergic receptor have indicated the importance of receptor phosphorylation in the desensitization phenomenon.119 Two type of desensitizing phosphorylation events have been described: homologous desensitization which involves phosphorylation of ligand-occupied receptors by G protein-coupled receptor kinases (GRK), and heterologous desensitization which involves phosphorylation of receptors unoccupied by ligand by protein kinase A. A family of at least 7 human genes encoding known or putative G protein-coupled receptor kinases has been identified by cDNA cloning.127,128 The best characterized members of this family, the β adrenergic receptor kinases (βARK) 1 and 2, and rhodopsin kinase, have been shown to function in a stimulus-dependent fashion for several different receptor substrates. βARK1 and βARK2 (GRK2 and 3), and the gene for a recently identified putative GRK designated GPRK6 are expressed in neutrophils, and all other human tissues examined. Genes for additional putative GRKs, designated GPRK5 and GPRK7, were identified by homology PCR in human neutrophils.128 GRKs translocate from the cytosol to their substrates on the plasma membrane in response to specific types of agonist stimulation. Given the large number of known G protein-coupled receptors, it will be interesting to determine whether they are regulated by a similarly large family of receptor kinases.
Summary and Development of a New Approach to Senescence
Published in Nate F. Cardarelli, The Thymus in Health and Senescence, 2019
The human fetal pineal and retina have similar cell types. In many species antigenic, enzymatic, and morphological relationships between pineal cells and retina have been observed. Rhodopsin kinase levels are high in eye and pineal, while very low or lacking in all other organs. Pineal cells in tissue culture will differentiate into retina-like cells containing lentoid bodies with 8 crystallin.112 The formation of lentoid bodies and crystallins in vitro is dependent upon the age of the tissue used, old cells in culture showing very low productivity.113
Supersensitivity and Desensitization
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Also present in crude preparations of β-ARK was a factor termed β-arrestin. This is analogous to arrestin, the 48 kDa protein that inactivates rhodopsin kinase in the rhodopsin photoreceptor system. β-ARK is comparable with rhodopsin kinase, the retinal enzyme that phosphorylates and inactivates only the light-bleached form of rhodopsin. Thus, arrestin inhibits transducin, the retinal G protein, from interacting with the phosphorylated rhodopsin. β-Arrestin interacts with the β-ARK phosphorylated receptor leading to enhanced uncoupling from the Gs regulatory protein. Therefore both β-ARK and β-arrestin are required for this agonist-specific phosphorylation and uncoupling process, leading to homologous desensitization. Human β-ARK has now been cloned and sequenced. It also interacts with the βγ-subunits of the G protein by the C-terminal portion of β-ARK. The β-ARK-βγ complex is thereby anchored in the cell membrane and allows for more efficient receptor phosphorylation and desensitization. This would occur when the receptors are activated to release the βτ-subunit and would thus facilitate termination of receptor activation through the phosphorylation process.
Envisioning the development of a CRISPR-Cas mediated base editing strategy for a patient with a novel pathogenic CRB1 single nucleotide variant
Published in Ophthalmic Genetics, 2022
J.-S. Bellingrath, M. E. McClements, M. Shanks, P. Clouston, M. D. Fischer, R. E. MacLaren
Since CRB1 is expressed in both the photoreceptors and the MCG, it raises the question which promotor could be used to target both cell types. Three common ubiquitous promotors, cytomegalovirus immediate-early promoter (CMV), human ubiquitin C promoter (UbiC), and chicken beta actin promoter (CAG), have showed a dose-dependent toxicity. This contrasts with cell-specific promotors such as rhodopsin kinase (RK), which did not show toxicity, even at high doses (72). The lack of CRB1 promotor flexibility and the resulting ectopic expression might also contribute to the deleterious effect of seen in pre-clinical CRB1 gene supplementation (5,25). Finding a suitable, representative model for CRB1-based disease is equally important for modeling mutations and their treatment options. While several naturally occurring and engineered mouse models exist (20,73–76), none of these models are suitable for testing a base editing strategy. Due to the species-specific differences between humans and mice, as well as the mild phenotype of Crb1 mutant mice, human induced pluripotent stem cells (hiPSC)-derived retinal organoids from CRB1 patients may be good models for testing base and gene editing strategies, as they have been shown to have a phenotype (21) and would more accurately mimic CRB1 localization and disease phenotype in humans.
The spermatogenesis-associated protein-7 (SPATA7) gene – an overview
Published in Ophthalmic Genetics, 2020
The potential of gene replacement therapy was tested in a Spata7 knockout mouse model by means of Spata7 gene delivery using the vector AAV8 (Y733F). This vector is a serotype of AAV8 reported to have an improved efficiency of transduction in the retina, especially in photoreceptors. Subretinal delivery of the Spata7 gene under the control of the human rhodopsin kinase promoter achieved expression of transgenic Spata7 in these mice, resulting in increased survival of photoreceptors, improvement in ERG responses and a rescue of the aberrant localization of rhodopsin as compared with untreated mutant mice (26). Feasibility of translation of these gene therapy studies for treating patients with SPATA7 mutations would depend first on successful application of the procedure in large mammals with SPATA7 gene knockdown, and on a gene delivery system that can reach a sustained high level of expression after therapy in humans. Trials of RPE65 gene delivery in the past have pointed to the success and challenges of gene replacement therapy (27).
RPGR gene therapy presents challenges in cloning the coding sequence
Published in Expert Opinion on Biological Therapy, 2020
Cristina Martinez-Fernandez De La Camara, Jasmina Cehajic-Kapetanovic, Robert E. MacLaren
The promoter of choice in these three clinical trials for RPGR is the rhodopsin kinase (RK or GRK1), well known for its high efficiency in driving transgene expression in rod and cone photoreceptors. The two main differences in the three gene therapy vectors are the coding sequence and the viral capsid. As discussed above, the version of the coding sequence being tested in these trials differs mainly on its ability to produce the full-length protein that is fully glutamylated (hence, functional).