A Role for Myocilin in Receptor-Mediated Endocytosis

McKay, Brian S.; Congrove, Nicole R.; Johnson, Adiv A.; Dismuke, W. Michael; Bowen, Trent J; Stamer, W. Daniel

doi:10.1371/journal.pone.0082301

Cited by 15 publications

(13 citation statements)

References 62 publications

(69 reference statements)

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“…Both exosomes and melanosomes are components of the endosomal compartment, and in both cases, GPR143 signaling appears to inhibit the membrane fusion of that compartment, but with different outcomes. In previous studies, we have shown that GPR143 signaling recruits the cytoplasmic protein myocilin to the endosomal compartment, where it is released from the cells on the surface of exosomes [29,52,53]. This observation provides direct evidence that GPR143 signaling causes cytoplasmic protein translocation to the exosome prior to release.…”

Section: Gpr143 Signalingsupporting

confidence: 52%

A G-Protein Coupled Receptor and Macular Degeneration

Figueroa

McKay

2020

Cells

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Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the world. The risk of AMD increases with age and is most common among the white population. Here, we discuss the convergence of factors related to race, pigmentation, and susceptibility to AMD, where the primary defect occurs in retinal support cells, the retinal pigment epithelium (RPE). We explore whether the observed racial bias in AMD incidence is related to innate differences in the basal level of pigmentation between races, and whether the pigmentation pathway activity in the RPE might protect from retinal degeneration. More specifically, we explore whether the downstream signaling activity of GPR143, a G-protein coupled receptor in the pigmentation pathway, might underly the racial bias of AMD and be a target to prevent the disease. Lastly, we summarize the past findings of a large retrospective study that investigated the relationship between the stimulation of GPR143 with L-DOPA, the pigmentation pathway, and AMD, to potentially help develop new ways to prevent or treat AMD. The reader of this review will come to understand the racial bias of AMD, which is related to the function of the RPE.

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Section: Gpr143 Signalingsupporting

confidence: 52%

A G-Protein Coupled Receptor and Macular Degeneration

Figueroa

McKay

2020

Cells

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“…Thus, caveolin-mediated endocytosis is one mechanism by which TM cells can alter the catabolism of ECM components and may contribute to the pathological changes that are observed in glaucomatous TM. A recent study showed that the archetypal glaucoma gene, myocilin, may also be involved in receptor-mediated endocytosis (McKay et al, 2013). …”

Section: Potential Mechanisms Leading To Ecm Changes In Glaucomatous Tmmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

Vranka

Kelley

Acott

et al. 2015

Experimental Eye Research

308

291

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The trabecular meshwork (TM) is located in the anterior segment of the eye and is responsible for regulating the outflow of aqueous humor. Increased resistance to aqueous outflow causes intraocular pressure to increase, which is the primary risk factor for glaucoma. TM cells reside on a series of fenestrated beams and sheets through which the aqueous humor flows to exit the anterior chamber via Schlemm’s canal. The outer trabecular cells are phagocytic and are thought to function as a pre-filter. However, most of the outflow resistance is thought to be from the extracellular matrix (ECM) of the juxtacanalicular region, the deepest portion of the TM, and from the inner wall basement membrane of Schlemm’s canal. It is becoming increasingly evident that the extracellular milieu is important in maintaining the integrity of the TM. Not only have ultrastructural changes been observed in the ECM of the TM in glaucoma, and a significant number of mutations in ECM genes are known to be associated with glaucoma, but the stiffness of glaucomatous TM appears to be greater than that of normal tissue. Additionally, TGFβ2 has been found to be elevated in the aqueous humor of glaucoma patients and is assumed to be involved in ECM changes deep with the juxtacanalicular region of the TM. This review summarizes the current literature on trabecular ECM as well as the development and function of the TM. Animal models and organ culture models targeting specific ECM molecules to investigate the mechanisms of glaucoma are described. Finally, the growing number of mutations that have been identified in ECM genes and genes that modulate ECM in humans with glaucoma are documented.

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“…Alternative hypotheses have been proposed to explain the deleterious cellular effects of MYOC mutations, such as altered association kinetics and co-localization with proteins in the endocytic pathway (e.g. (Hardy et al, 2005; McKay et al, 2013)).…”

Section: Myocilinmentioning

confidence: 99%

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Fini

Schwartz

Gao

et al. 2017

Progress in Retinal and Eye Research

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121

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Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative®, announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine.

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A Role for Myocilin in Receptor-Mediated Endocytosis

Cited by 15 publications

References 62 publications

A G-Protein Coupled Receptor and Macular Degeneration

A G-Protein Coupled Receptor and Macular Degeneration

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

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