Limits...
Through a glass darkly.

Hall JE - EMBO Mol Med (2011)

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, University of California, Irvine, CA, USA. jhall@uci.edu

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See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201100184 The clarity of the ocular lens stands in stark contrast to the obscurity of our understanding of lens physiology, but there are encouraging signs that the darkness may be lifting... In showing first that AKAP2 lures PKA into close proximity with AQP0 and second that PKA from this association leads to loss of cortical transparency, this paper establishes clearly a link between a regulatory pathway and maintenance of lens clarity... Though Gold et al, and common sense strongly argue that regulation of water permeability (probably as one of multiple feedback loops in the control of the circulation of fluid) is essential for clarity, the nature of the feedback loops and how they are closed remains a mystery... Its concentration increases toward the centre of the lens and increases markedly in cortical cataract (Duncan et al, )... But how is change in calcium concentration coupled to a need for increased or decreased water permeability, and how is the link between osmotically driven flow through AQP0 and hydrostatic pressure driven flow through gap junctions maintained? It has been demonstrated in vitro (Németh-Cahalan & Hall, ), but does it have physiological importance? We know pH is more acidic by a pH unit or so in the interior than on the surface, but we do not know if this is used as a regulatory signal... And what about the association of AQP0 with connexin 50 (Yu & Jiang, ; Zampighi et al, )? Could the regulation of AQP0 by the complex described by Gold et al, be directly communicated to the gap junctional complex or does connexin 50 have its own suite of regulatory proteins? The good news is that Gold et al, have shown us that a regulatory mechanism of one of the principal players in the fluid balance of the lens is essential for lens clarity, and they suggest that investigating other interactions of AKAP proteins in the lens may be fruitful... Their observations underscore the necessity of studying the lens as a system of interacting components not as a collection of independent proteins going their own way... So as always, the price paid for an increase in knowledge is an increase in the number of questions we never knew existed.

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Elements of the fluid circulation modelThe regulatory complex described by Gold et al, 2011 is enclosed in a dashed rectangle. Transporters, channels, pumps and gap junctions are shown in the right hand panel that depicts the membranes of epithelial cells and cortical fibre cells. The left hand panel shows the proposed inward flow of ions, water and nutrients through the interstitium and the outward intracellular flow through gap junctions. While the regulation of AQP0 by the mechanism described by Gold et al, 2011 is essential for lens clarity, just how the feedback loops controlling the circulation described operate remains obscure. E, epithelial cells; DF, developing fibre cells; MF, mature fibre cells (Figure modified after Donaldson et al, 2001).
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fig01: Elements of the fluid circulation modelThe regulatory complex described by Gold et al, 2011 is enclosed in a dashed rectangle. Transporters, channels, pumps and gap junctions are shown in the right hand panel that depicts the membranes of epithelial cells and cortical fibre cells. The left hand panel shows the proposed inward flow of ions, water and nutrients through the interstitium and the outward intracellular flow through gap junctions. While the regulation of AQP0 by the mechanism described by Gold et al, 2011 is essential for lens clarity, just how the feedback loops controlling the circulation described operate remains obscure. E, epithelial cells; DF, developing fibre cells; MF, mature fibre cells (Figure modified after Donaldson et al, 2001).

Mentions: The clarity of the ocular lens stands in stark contrast to the obscurity of our understanding of lens physiology, but there are encouraging signs that the darkness may be lifting. There is increasing experimental support for the fluid circulation model (Fig 1) first proposed by Mathias & Rae, 1985 and more recently expanded by Mathias et al, 2007. The first experimentally verified predictions of the model were that as one approaches the centre of the lens the intracellular voltage should be increasingly positive and the extracellular voltage increasingly negative (Mathias & Rae, 1985). Much later diffusion tensor imaging and measurement of external circulating currents showed that both water entry (Vaghefi et al, 2011) and external circulating current (first measured by Robinson & Patterson, 1983) were eliminated by high external potassium. And in the past year Mathias and colleagues have shown that the internal pressure of the lens is about a third of an atmosphere at the centre of the lens, decreasing away from the centre until it reaches zero at the surface (Gao et al, 2011). This pressure is inversely proportional to the number of gap junctions distributed throughout the fibre cells in the interior of the lens, a finding that not only strongly supports the fluid circulation model but also provides the most direct evidence yet that water moves through gap junctions.


Through a glass darkly.

Hall JE - EMBO Mol Med (2011)

Elements of the fluid circulation modelThe regulatory complex described by Gold et al, 2011 is enclosed in a dashed rectangle. Transporters, channels, pumps and gap junctions are shown in the right hand panel that depicts the membranes of epithelial cells and cortical fibre cells. The left hand panel shows the proposed inward flow of ions, water and nutrients through the interstitium and the outward intracellular flow through gap junctions. While the regulation of AQP0 by the mechanism described by Gold et al, 2011 is essential for lens clarity, just how the feedback loops controlling the circulation described operate remains obscure. E, epithelial cells; DF, developing fibre cells; MF, mature fibre cells (Figure modified after Donaldson et al, 2001).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376833&req=5

fig01: Elements of the fluid circulation modelThe regulatory complex described by Gold et al, 2011 is enclosed in a dashed rectangle. Transporters, channels, pumps and gap junctions are shown in the right hand panel that depicts the membranes of epithelial cells and cortical fibre cells. The left hand panel shows the proposed inward flow of ions, water and nutrients through the interstitium and the outward intracellular flow through gap junctions. While the regulation of AQP0 by the mechanism described by Gold et al, 2011 is essential for lens clarity, just how the feedback loops controlling the circulation described operate remains obscure. E, epithelial cells; DF, developing fibre cells; MF, mature fibre cells (Figure modified after Donaldson et al, 2001).
Mentions: The clarity of the ocular lens stands in stark contrast to the obscurity of our understanding of lens physiology, but there are encouraging signs that the darkness may be lifting. There is increasing experimental support for the fluid circulation model (Fig 1) first proposed by Mathias & Rae, 1985 and more recently expanded by Mathias et al, 2007. The first experimentally verified predictions of the model were that as one approaches the centre of the lens the intracellular voltage should be increasingly positive and the extracellular voltage increasingly negative (Mathias & Rae, 1985). Much later diffusion tensor imaging and measurement of external circulating currents showed that both water entry (Vaghefi et al, 2011) and external circulating current (first measured by Robinson & Patterson, 1983) were eliminated by high external potassium. And in the past year Mathias and colleagues have shown that the internal pressure of the lens is about a third of an atmosphere at the centre of the lens, decreasing away from the centre until it reaches zero at the surface (Gao et al, 2011). This pressure is inversely proportional to the number of gap junctions distributed throughout the fibre cells in the interior of the lens, a finding that not only strongly supports the fluid circulation model but also provides the most direct evidence yet that water moves through gap junctions.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, University of California, Irvine, CA, USA. jhall@uci.edu

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201100184 The clarity of the ocular lens stands in stark contrast to the obscurity of our understanding of lens physiology, but there are encouraging signs that the darkness may be lifting... In showing first that AKAP2 lures PKA into close proximity with AQP0 and second that PKA from this association leads to loss of cortical transparency, this paper establishes clearly a link between a regulatory pathway and maintenance of lens clarity... Though Gold et al, and common sense strongly argue that regulation of water permeability (probably as one of multiple feedback loops in the control of the circulation of fluid) is essential for clarity, the nature of the feedback loops and how they are closed remains a mystery... Its concentration increases toward the centre of the lens and increases markedly in cortical cataract (Duncan et al, )... But how is change in calcium concentration coupled to a need for increased or decreased water permeability, and how is the link between osmotically driven flow through AQP0 and hydrostatic pressure driven flow through gap junctions maintained? It has been demonstrated in vitro (Németh-Cahalan & Hall, ), but does it have physiological importance? We know pH is more acidic by a pH unit or so in the interior than on the surface, but we do not know if this is used as a regulatory signal... And what about the association of AQP0 with connexin 50 (Yu & Jiang, ; Zampighi et al, )? Could the regulation of AQP0 by the complex described by Gold et al, be directly communicated to the gap junctional complex or does connexin 50 have its own suite of regulatory proteins? The good news is that Gold et al, have shown us that a regulatory mechanism of one of the principal players in the fluid balance of the lens is essential for lens clarity, and they suggest that investigating other interactions of AKAP proteins in the lens may be fruitful... Their observations underscore the necessity of studying the lens as a system of interacting components not as a collection of independent proteins going their own way... So as always, the price paid for an increase in knowledge is an increase in the number of questions we never knew existed.

Show MeSH