Calcium ATPase activity and membrane structure in clear and cataractous human lenses

Paterson, Christopher A.; Zeng, Junwen; Husseini, Ziad M.; Borchman, Douglas; Delamere, Nicholas A.; Garland, Donita; Jimenez-Asensio, Jose

doi:10.1076/ceyr.16.4.333.10689

Cited by 75 publications

(54 citation statements)

References 8 publications

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“…Conversely, in human lenses with cataract, Ca 2þ -ATPase activity was reduced by 50% compared to clear lenses (Paterson et al, 1997) although overall expression in cataractous lenses was unchanged. Recently, upregulation of PMCA2 was reported in the epithelia of cataractous lenses, presumably in compensation for increased intracellular Ca 2þ levels (Marian et al, 2008).…”

Section: The Plasma Membrane Ca 2þ -Atpasementioning

confidence: 88%

“…All 4 PMCA isoforms are expressed in both bovine (Bian et al, 2000) and human (Marian et al, 2007) lens epithelial cells and although multiple splice variants have been identified in other tissues there is, as yet, no evidence that this is the case in the lens (Bian et al, 2000). Early reports indicated Ca 2þ -ATPase activity in both epithelial cells and cortical fibres (Hightower et al, 1980;Borchman et al, 1989), although, more recent studies suggest that expression and activity are limited to the epithelium (Paterson et al, 1997;Marian et al, 2005).…”

Section: The Plasma Membrane Ca 2þ -Atpasementioning

confidence: 99%

“…Increasing lipid order, and hence membrane stiffness, has also been shown to increase PMCA activity (Tang et al, 2006). It is significant that lipid order has been shown to increase with age and cataract (Paterson et al, 1997) and PMCA activity might, therefore, also be expected to increase in these conditions. It remains to be elucidated, however, in exactly what capacity PMCA activity contributes to cataract: whether through upregulation, to mitigate increases in intracellular Ca 2þ , or through loss of activity contributing to cataractogenic Ca 2þ overload.…”

Section: The Plasma Membrane Ca 2þ -Atpasementioning

confidence: 99%

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The mechanisms of calcium homeostasis and signalling in the lens

Rhodes

Sanderson

2009

Experimental Eye Research

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a b s t r a c tExcessive Ca 2þ can be detrimental to cells and raised levels of Ca 2þ in human lenses with cortical cataract have been found to play a major role in the opacification process. Ca 2þ homeostasis is therefore, recognised as having fundamental importance in lens pathophysiology. Furthermore, Ca 2þ plays a central role as a second messenger in cell signalling and mechanisms have evolved which give cells exquisite control over intracellular Ca 2þ ([Ca 2þ ] i ) via an array of specialised regulatory and signalling proteins. In this review we discuss these mechanisms as they apply to the lens. Ca 2þ levels in human aqueous humour are approximately 1 mM and there is a large, 10,000 fold, inwardly directed gradient across the plasma membrane. In the face of such a large gradient highly efficient mechanisms are needed to maintain low [Ca 2þ ] i . The Na þ /Ca 2þ exchanger (NCX) and plasma membrane Ca 2þ -ATPase (PMCA) actively remove Ca 2þ from the cells, whereas the sarco(endo)plasmic reticulum Ca 2þ -ATPase (SERCA) sequesters Ca 2þ in the endoplasmic reticulum (ER) Ca 2þ store. In lens epithelial cells the dominant role is played by the ATPases, whilst in the fibre cells NCX activity appears to be more important. Usually, [Ca 2þ ] i can be increased in a number of ways. Ca 2þ influx through the plasma membrane, for example, is mediated by an array of channels with evidence in the lens for the presence of voltage-operated Ca 2þ channels (VOCCs), receptor-operated Ca 2þ channels (ROCCs) and channels mediating store-operated Ca 2þ entry (SOCE). Ca 2þ signalling is initiated via activation of G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTK) of which the lens expresses a surprisingly diverse array responding to various neurotransmitters, hormones, growth factors, autocoids and proteases. Downstream of plasma membrane receptors are IP 3 -gated channels (IP 3 Rs) and ryanodine receptors (RYRs) located in the ER, which when activated cause a rapid increase in [Ca 2þ ] i and these have also been identified in the lens. Through an appreciation of the diversity and complexity of the mechanisms involved in Ca 2þ homeostasis in normal lens cells we move closer to an understanding of the mechanisms which mediate pathological Ca 2þ overload as occurs in the process of cataract formation.

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Section: The Plasma Membrane Ca 2þ -Atpasementioning

confidence: 88%

Section: The Plasma Membrane Ca 2þ -Atpasementioning

confidence: 99%

Section: The Plasma Membrane Ca 2þ -Atpasementioning

confidence: 99%

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The mechanisms of calcium homeostasis and signalling in the lens

Rhodes

Sanderson

2009

Experimental Eye Research

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“…In particular, a PQ type voltage gated calcium channel was detected to be increased in cataract by nearly 5-fold. Calcium is likely to be an important factor in cataract formation since the activity of calcium-ATPase is reduced by 50% in the membranes of lens epithelia isolated from cataractous lenses compared to clear human lenses (Paterson et al, 1997). Oxidative stress has also been demonstrated to have an effect on the activity of calcium transporters in the lens.…”

Section: Gene Expression Profiles Of Human Age-related Cataractsmentioning

confidence: 99%

Identification and functional clustering of global gene expression differences between age-related cataract and clear human lenses and aged human lenses

Hawse

Hejtmancik

Horwitz

et al. 2004

Experimental Eye Research

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We have examined the gene expression profiles of young, old and cataractous human lenses in order to differentiate those gene expression changes specific for cataract from those also associated with lens aging. Differentially expressed transcripts were identified by oligonucleotide microarray analysis and clustered according to their known functions. Four hundred and twelve transcripts that are increased and 919 transcripts that are decreased were identified at the 2-fold or greater level between epithelia isolated from cataract relative to clear lenses while 182 transcripts that are increased and 547 transcripts that are decreased were identified at the 2-fold or greater level between young and old lens epithelia. Comparison of the cataract gene expression changes with those detected in lens aging revealed that only 3 transcripts exhibited similar trends in gene expression. These data suggest that cataract-and age-specific changes in gene expression do not overlap and provide evidence for multiple cataract-and age-specific gene expression changes in the human lens.

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“…Several forms of cataracts are directly associated with perturbations in the levels of calcium within the lens, indicating a potential role for the calcium dependent cysteine proteases known as calpains (15)(16)(17). Numerous reports have described the use of a general cysteine protease inhibitor, E-64, in experimental studies of cataract formation.…”

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confidence: 99%

Defining a Link between Gap Junction Communication, Proteolysis, and Cataract Formation

Baruch¹,

Greenbaum²,

Levy³

et al. 2001

Journal of Biological Chemistry

103

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Disruption of the connexin ␣3 (Cx46) gene (␣3 (؊/؊)) in mice results in severe cataracts within the nuclear portion of the lens. These cataracts are associated with proteolytic processing of the abundant lens protein ␥-crystallin, leading to its aggregation and subsequent opacification of the lens. The general cysteine protease inhibitor, E-64, blocked cataract formation and ␥-crystallin cleavage in ␣3 (؊/؊) lenses. Using a new class of activity-based cysteine protease affinity probes, we identified the calcium-dependent proteases, m-calpain and Lp82, as the primary targets of E-64 in the lens. Profiling changes in protease activities throughout cataractogenesis indicated that Lp82 activity was dramatically increased in ␣3 (؊/؊) lenses and correlated both spatially and temporally with cataract formation. Increased Lp82 activity was due to calcium accumulation as a result of increased influx and decreased outflux of calcium ions in ␣3 (؊/؊) lenses. These data establish a role for ␣3 gap junctions in maintaining calcium homeostasis that in turn is required to control activity of the calcium-dependent cysteine protease Lp82, shown here to be a key initiator of the process of cataractogenesis.

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Calcium ATPase activity and membrane structure in clear and cataractous human lenses

Abstract: These findings support the hypothesis that membranes are deranged in cataractous tissue, which should lead to altered levels of calcium.

Cited by 75 publications

References 8 publications

The mechanisms of calcium homeostasis and signalling in the lens

The mechanisms of calcium homeostasis and signalling in the lens

Identification and functional clustering of global gene expression differences between age-related cataract and clear human lenses and aged human lenses

Defining a Link between Gap Junction Communication, Proteolysis, and Cataract Formation

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