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Involvement of A(1) adenosine receptors in osmotic volume regulation of retinal glial cells in mice.

Wurm A, Lipp S, Pannicke T, Linnertz R, Färber K, Wiedemann P, Reichenbach A, Bringmann A - Mol. Vis. (2009)

Bottom Line: The size of Müller cell somata was recorded before and during perfusion of retinal sections and isolated Müller cells with a hypoosmolar solution.The data suggest that autocrine activation of A(1) receptors by extracellularly generated adenosine mediates the volume homeostasis of Müller cells in the murine retina.The swelling-inhibitory effect of triamcinolone is mediated by enhancement of endogenous adenosine signaling.

View Article: PubMed Central - PubMed

Affiliation: Paul Flechsig Institute of Brain Research, University of Leipzig, D-04103 Leipzig, Germany.

ABSTRACT

Purpose: Osmotic swelling of Müller glial cells has been suggested to contribute to retinal edema. We determined the role of adenosine signaling in the inhibition of Müller cell swelling in the murine retina.

Methods: The size of Müller cell somata was recorded before and during perfusion of retinal sections and isolated Müller cells with a hypoosmolar solution. Retinal tissues were freshly isolated from wild-type mice and mice deficient in A(1) adenosine receptors (A(1)AR(-/-)), or cultured as whole-mounts for three days. The potassium conductance of Müller cells was recorded in isolated cells, and retinal slices were immunostained against Kir4.1.

Results: Hypotonic exposure for 4 min induced a swelling of Müller cell bodies in retinal slices from A(1)AR(-/-) mice but not wild-type mice. Pharmacological inhibition of A(1) receptors or of the ecto-5'-nucleotidase induced hypoosmotic swelling of Müller cells from wild-type mice. Exogenous adenosine prevented the swelling of Müller cells from wild-type but not A(1)AR(-/-) mice. The antiinflammatory corticosteroid, triamcinolone acetonide, inhibited the swelling of Müller cells from wild-type mice; this effect was blocked by an antagonist of A(1) receptors. The potassium conductance of Müller cells and the Kir4.1 immunolabeling of retinal slices were not different between A(1)AR(-/-) and wild-type mice, both in freshly isolated tissues and retinal organ cultures.

Conclusions: The data suggest that autocrine activation of A(1) receptors by extracellularly generated adenosine mediates the volume homeostasis of Müller cells in the murine retina. The swelling-inhibitory effect of triamcinolone is mediated by enhancement of endogenous adenosine signaling.

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Involvement of adenosine signaling in the endogenous osmotic volume regulation of retinal glial cells in mice. Adenosine, which is extracellularly formed from AMP by the action of CD73, activates A1 receptors of Müller cells. Activation of the receptors triggers (via intracellular formation of cAMP) the opening of potassium and chloride channels in the Müller cell membrane. The ion efflux from the cells equalizes the osmotic gradient across the plasma membrane and thus prevents cellular swelling under hypotonic conditions. Different steps of the signaling cascade can be blocked by specific antagonists (shown in white), resulting in cellular swelling when the extracellular osmolarity decreases.
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f6: Involvement of adenosine signaling in the endogenous osmotic volume regulation of retinal glial cells in mice. Adenosine, which is extracellularly formed from AMP by the action of CD73, activates A1 receptors of Müller cells. Activation of the receptors triggers (via intracellular formation of cAMP) the opening of potassium and chloride channels in the Müller cell membrane. The ion efflux from the cells equalizes the osmotic gradient across the plasma membrane and thus prevents cellular swelling under hypotonic conditions. Different steps of the signaling cascade can be blocked by specific antagonists (shown in white), resulting in cellular swelling when the extracellular osmolarity decreases.

Mentions: Regulation of the Müller cell volume has great importance for the homeostasis of the extracellular space volume under conditions of intense neuronal activity. It has been shown that activation of neuronal ionotropic glutamate receptors causes a net uptake of sodium chloride, resulting in a swelling of neuronal cell bodies and synapses, and a decrease in the extracellular space volume [38]. Light-evoked changes in the ionic composition of the extracellular space fluid, with a decrease in sodium which is about twice as large as the increase in potassium, cause a decrease in the osmolarity of the extracellular fluid [39]. The uptake of neuron-derived osmolytes, such as potassium and sodium glutamate [37,40], may further enhance the osmotic gradient across Müller cell membranes. To avoid an excessive decrease in the extracellular space volume, which may result in neuronal hyperexcitability [41,42], Müller cells must maintain their volume constant, or decrease their volume, when neuronal cell structures swell and the extracellular osmolarity decreases during neuronal activity. The present results suggest that, in the murine retina, an endogenous adenosine signaling mediates the volume homeostasis of Müller cells in response to varying osmotic conditions. A disruption of this signaling by pharmacological inhibition of A1 receptors or targeted deletion of A1 receptors results in a swelling of Müller cells when the environment is hypoosmolar in comparison to the Müller cell interior. The present data suggest that CD73-dependent extracellular production of adenosine, activation of A1 receptors, an increase in cytosolic cAMP, and an opening of potassium and chloride channels are events in mediating the volume homeostasis of Müller cells in the mouse retina (Figure 6). The swelling of Müller cells from A1AR−/− mice (Figure 4A) and of wild-type cells during pharmacological blockade of A1 receptors (Figures 3A,B), and the absence of a swelling-inhibitory effect of adenosine in cells from A1AR−/− mice (Figure 4B), suggest that other receptor systems cannot compensate the missing action of A1 receptors in the regulation of Müller cell volume.


Involvement of A(1) adenosine receptors in osmotic volume regulation of retinal glial cells in mice.

Wurm A, Lipp S, Pannicke T, Linnertz R, Färber K, Wiedemann P, Reichenbach A, Bringmann A - Mol. Vis. (2009)

Involvement of adenosine signaling in the endogenous osmotic volume regulation of retinal glial cells in mice. Adenosine, which is extracellularly formed from AMP by the action of CD73, activates A1 receptors of Müller cells. Activation of the receptors triggers (via intracellular formation of cAMP) the opening of potassium and chloride channels in the Müller cell membrane. The ion efflux from the cells equalizes the osmotic gradient across the plasma membrane and thus prevents cellular swelling under hypotonic conditions. Different steps of the signaling cascade can be blocked by specific antagonists (shown in white), resulting in cellular swelling when the extracellular osmolarity decreases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2743807&req=5

f6: Involvement of adenosine signaling in the endogenous osmotic volume regulation of retinal glial cells in mice. Adenosine, which is extracellularly formed from AMP by the action of CD73, activates A1 receptors of Müller cells. Activation of the receptors triggers (via intracellular formation of cAMP) the opening of potassium and chloride channels in the Müller cell membrane. The ion efflux from the cells equalizes the osmotic gradient across the plasma membrane and thus prevents cellular swelling under hypotonic conditions. Different steps of the signaling cascade can be blocked by specific antagonists (shown in white), resulting in cellular swelling when the extracellular osmolarity decreases.
Mentions: Regulation of the Müller cell volume has great importance for the homeostasis of the extracellular space volume under conditions of intense neuronal activity. It has been shown that activation of neuronal ionotropic glutamate receptors causes a net uptake of sodium chloride, resulting in a swelling of neuronal cell bodies and synapses, and a decrease in the extracellular space volume [38]. Light-evoked changes in the ionic composition of the extracellular space fluid, with a decrease in sodium which is about twice as large as the increase in potassium, cause a decrease in the osmolarity of the extracellular fluid [39]. The uptake of neuron-derived osmolytes, such as potassium and sodium glutamate [37,40], may further enhance the osmotic gradient across Müller cell membranes. To avoid an excessive decrease in the extracellular space volume, which may result in neuronal hyperexcitability [41,42], Müller cells must maintain their volume constant, or decrease their volume, when neuronal cell structures swell and the extracellular osmolarity decreases during neuronal activity. The present results suggest that, in the murine retina, an endogenous adenosine signaling mediates the volume homeostasis of Müller cells in response to varying osmotic conditions. A disruption of this signaling by pharmacological inhibition of A1 receptors or targeted deletion of A1 receptors results in a swelling of Müller cells when the environment is hypoosmolar in comparison to the Müller cell interior. The present data suggest that CD73-dependent extracellular production of adenosine, activation of A1 receptors, an increase in cytosolic cAMP, and an opening of potassium and chloride channels are events in mediating the volume homeostasis of Müller cells in the mouse retina (Figure 6). The swelling of Müller cells from A1AR−/− mice (Figure 4A) and of wild-type cells during pharmacological blockade of A1 receptors (Figures 3A,B), and the absence of a swelling-inhibitory effect of adenosine in cells from A1AR−/− mice (Figure 4B), suggest that other receptor systems cannot compensate the missing action of A1 receptors in the regulation of Müller cell volume.

Bottom Line: The size of Müller cell somata was recorded before and during perfusion of retinal sections and isolated Müller cells with a hypoosmolar solution.The data suggest that autocrine activation of A(1) receptors by extracellularly generated adenosine mediates the volume homeostasis of Müller cells in the murine retina.The swelling-inhibitory effect of triamcinolone is mediated by enhancement of endogenous adenosine signaling.

View Article: PubMed Central - PubMed

Affiliation: Paul Flechsig Institute of Brain Research, University of Leipzig, D-04103 Leipzig, Germany.

ABSTRACT

Purpose: Osmotic swelling of Müller glial cells has been suggested to contribute to retinal edema. We determined the role of adenosine signaling in the inhibition of Müller cell swelling in the murine retina.

Methods: The size of Müller cell somata was recorded before and during perfusion of retinal sections and isolated Müller cells with a hypoosmolar solution. Retinal tissues were freshly isolated from wild-type mice and mice deficient in A(1) adenosine receptors (A(1)AR(-/-)), or cultured as whole-mounts for three days. The potassium conductance of Müller cells was recorded in isolated cells, and retinal slices were immunostained against Kir4.1.

Results: Hypotonic exposure for 4 min induced a swelling of Müller cell bodies in retinal slices from A(1)AR(-/-) mice but not wild-type mice. Pharmacological inhibition of A(1) receptors or of the ecto-5'-nucleotidase induced hypoosmotic swelling of Müller cells from wild-type mice. Exogenous adenosine prevented the swelling of Müller cells from wild-type but not A(1)AR(-/-) mice. The antiinflammatory corticosteroid, triamcinolone acetonide, inhibited the swelling of Müller cells from wild-type mice; this effect was blocked by an antagonist of A(1) receptors. The potassium conductance of Müller cells and the Kir4.1 immunolabeling of retinal slices were not different between A(1)AR(-/-) and wild-type mice, both in freshly isolated tissues and retinal organ cultures.

Conclusions: The data suggest that autocrine activation of A(1) receptors by extracellularly generated adenosine mediates the volume homeostasis of Müller cells in the murine retina. The swelling-inhibitory effect of triamcinolone is mediated by enhancement of endogenous adenosine signaling.

Show MeSH
Related in: MedlinePlus