Calcium Signalling in Ocular Tissues: Functional Activity of G-protein and Tyrosine–Kinase Coupled Receptors

Duncan, G.; Collison, David

doi:10.1006/exer.2002.2033

Cited by 13 publications

(8 citation statements)

References 88 publications

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“…The mechanisms underlying such calcifications are not known, but the identification of CaSR expression in the lens epithelial cells (27) ] i triggers the activation of calpain, which in turn modifies the cytoskeletal proteins and a ␤-crystallin in lens cataract models (28,29). Moreover, the lens possesses a large array of G protein receptors that are coupled to the release of Ca 2ϩ (30,31), including CaSR, which has been shown to be expressed in human lens epithelial cells (27). Thus, it is possible that the Q723 mutant CaSR of the Nuf͞ϩ and Nuf͞Nuf mice results in activation at a lower [Ca 2ϩ ] o (Fig.…”

Section: Discussionmentioning

confidence: 99%

Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification

Hough

Bogani²,

Cheeseman³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

128

157

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The extracellular calcium-sensing receptor (CaSR) plays a pivotal role in the regulation of extracellular calcium such that abnormalities, which result in a loss or gain of function, lead to hypercalcemia or hypocalcemia, respectively, in patients. Mice carrying CaSR knockout alleles develop hypercalcemia that mimics the disorders observed in humans. To date, there is no mouse model for an activating CaSR mutation. Here, we describe such a mouse model, named Nuf, originally identified for having opaque flecks in the nucleus of the lens in a screen for eye mutants. Nuf mice also display ectopic calcification, hypocalcemia, hyperphosphatemia, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with autosomal dominant hypocalcemia. Inheritance studies of Nuf mice revealed that the trait was transmitted in an autosomal-dominant manner, and mapping studies located the locus to chromosome 16, in the vicinity of the CaSR gene (Mouse Genome Database symbol Gprc2a). DNA sequence analysis revealed the presence of a Gprc2a missense mutation, Leu723Gln. Transient expression of wild-type and mutant CaSRs in human embryonic kidney 293 cells demonstrated that the mutation resulted in a gain of function of the CaSR, which had a significantly lower EC 50. Thus, our results have identified a mouse model for an activating CaSR mutation, and the development of ectopic calcification and cataract formation, which tended to be milder in the heterozygote Nuf mice, indicates that an evaluation for such abnormalities in autosomal dominant hypocalcemia patients who have activating CaSR mutations is required.

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Section: Discussionmentioning

confidence: 99%

Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification

Hough

Bogani²,

Cheeseman³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

128

157

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“…CE is a stratified epithelium comprised of morphologically and functionally distinct epithelial cell types that represent stages in a continuum of transitional forms ranging from stem cells to surface epithelial cells (Cenedella and Fleschner 1990;Hanna et al 1961). As CE undergoes renewal, there is a constant production of cells that differ in proliferative capacity and differentiated properties and that vary in Ca 2+ -handling properties (Duncan and Collison 2002;Kimura et al 1999). The processes of CE renewal and wound healing involve a coordinated sequence of physiological events including cell migration, proliferation and differentiation (Thoft and Friend 1975), all of which depend on calcium-mediated processes (Cox and Huttenlocher 1998;Hazelton et al 1979;Shurman et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Alternative splice variants of plasma membrane calcium-ATPases in human corneal epithelium

Talarico

Mangini

2007

Experimental Eye Research

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Plasma membrane calcium-ATPases (PMCAs) play a critical role in regulating intracellular calcium concentration. Four genes encode PMCA proteins with alternative splicing of transcripts at three sites (A, B and C) serving to increase isoform diversity. Our previous work shows that all four PMCAs are expressed and have specific locations in human corneal epithelium (hCE). The present work examined which splice variants of PMCAs are expressed in hCE. Total RNA was extracted from hCE scraped from cadaver corneas of five different donors (two females and three males, age range 55 to 76 years). RT-PCR was performed using PMCA isoform-specific primers designed to amplify transcripts that included either splice site A or splice sites B and C. PMCA cDNAs were sequenced or cloned, and then sequenced. There was uniformity in the PMCA1 and PMCA4 expression profile among the five donors. Specifically, every donor expressed PMCA4 transcripts (4x at site A and 4b at site B/C). Every donor also expressed PMCA1 transcripts at sites B/C, specifically PMCA1b and PMCA1kb. In contrast, PMCA2 and PMCA3 expression varied; PCR DNAs were detected in two of five donors. One donor expressed PMCA2a and a novel PMCA2 variant we termed PMCA2 (i) . PMCA3a transcript was demonstrated in a different donor. Finally, for all the donors, bands encoding site A transcripts for PMCA4 were obtained but no PCR transcripts were detected at site A for PMCA1, PMCA2 and PMCA3. This investigation showed that hCE expressed multiple splice variants of PMCA isoforms. Furthermore, this study documented the expression of the PMCA1k variant (PMCA1kb) previously only described in intestine and pancreatic beta cells and describes a novel PMCA2 (i) variant. Finally, this study suggests that the molecular configuration of PMCA 1, 2 and 3 in the region of splice site A in hCE must be different than in other tissues since the same primers that produced site A transcripts in several other tissues were ineffective in priming PCR in hCE.

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“…The lens expresses several GPCRs whose activity has been implicated in the regulation of calcium fluxes or the calcium current in this ocular tissue (116). Bioactive lysophospholipids (sphingosin-1-phosphate and lysophosphatidic acid) play key roles in the regulation of fundamental cellular processes including proliferation, survival and migration.…”

Section: Rhomentioning

confidence: 99%

“…Using both pharmacological and molecular approaches, we evaluated the regulation of Rho GTPase activity in lens epithelial cells, and explored the potential role of the Rho-GTPases in lens development and function. In addition to Rho GTPases, calcium dependent pathways, (116), src kinases (96), PI3 kinase (117), Cdk5 (118), PDZ domain proteins (119), c-abl interactor proteins (73) and Wnt/frizzled signaling (120,121) pathways, all of which influence actin cytoskeletal dynamics and cell adhesions, are also considered to be important for lens cell migration, elongation and differentiation.…”

Section: Regulation Of Lens Actin Cytoskeletal Organizationmentioning

confidence: 99%

The role of the lens actin cytoskeleton in fiber cell elongation and differentiation

Rao

Maddala

2006

Seminars in Cell & Developmental Biology

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The vertebrate ocular lens is a fascinating and unique transparent tissue that grows continuously throughout life. During the process of differentiation into fiber cells, lens epithelial cells undergo dramatic morphological changes, membrane remodeling, polarization, transcriptional activation and elimination of cellular organelles including nuclei, concomitant with migration towards the lens interior. Most of these events are presumed to be influenced in large part, by dynamic reorganization of the cellular actin cytoskeleton and by intercellular and cell: extracellular matrix interactions. In light of recent and unprecedented advancement in our understanding of the mechanistic bases underlying regulation of actin cytoskeletal dynamics and the role of the actin cytoskeleton in cell function, this review attempts to summarize current knowledge regarding the role of the cellular actin cytoskeleton, in lens fiber cell elongation and differentiation, and regulation of actin cytoskeletal organization in the lens.

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Calcium Signalling in Ocular Tissues: Functional Activity of G-protein and Tyrosine–Kinase Coupled Receptors

Cited by 13 publications

References 88 publications

Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification

Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification

Alternative splice variants of plasma membrane calcium-ATPases in human corneal epithelium

The role of the lens actin cytoskeleton in fiber cell elongation and differentiation

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