Abstract
BackgroundGlial cells such as retinal Müller glial cells are involved in potassium ion and water homeostasis of the neural tissue. In these cells, inwardly rectifying potassium (Kir) channels and aquaporin-4 water channels play an important role in the process of spatial potassium buffering and water drainage. Moreover, Kir4.1 channels are involved in the maintenance of the negative Müller cell membrane potential. The subcellular distribution of Kir4.1 and aquaporin-4 channels appears to be maintained by interactions with extracellular and intracellular molecules. Laminins in the extracellular matrix, dystroglycan in the membrane, and dystrophins in the cytomatrix form a complex mediating the polarized expression of Kir4.1 and aquaporin-4 in Müller cells.Methodology/Principal FindingsThe aim of the present study was to test the function of the β2 and γ3 containing laminins in murine Müller cells. We used knockout mice with genetic deletion of both β2 and γ3 laminin genes to assay the effects on Kir4.1 and aquaporin-4. We studied protein and mRNA expression by immunohistochemistry, Western Blot, and quantitative RT-PCR, respectively, and membrane currents of isolated cells by patch-clamp experiments. We found a down-regulation of mRNA and protein of Kir4.1 as well as of aquaporin-4 protein in laminin knockout mice. Moreover, Müller cells from laminin β2 and γ3 knockout mice had reduced Kir-mediated inward currents and their membrane potentials were more positive than those in age-matched wild-type mice.ConclusionThese findings demonstrate a strong impact of laminin β2 and γ3 subunits on the expression and function of both aquaporin-4 and Kir4.1, two important membrane proteins in Müller cells.
Highlights
In the murine retina, Muller cells constitute the dominant macroglia
These findings demonstrate a strong impact of laminin b2 and c3 subunits on the expression and function of both aquaporin-4 and Kir4.1, two important membrane proteins in Muller cells
The important role of the Kir4.1 channels is demonstrated by a number of studies identifying mutations in the Kir4.1 gene (KCNJ10) as a reason for symptoms found in the EAST syndrome [14,15,16,17,18]
Summary
Muller cells constitute the dominant macroglia. Muller cells are specialized radial glial cells which span the entire thickness of the retina. In the diseased retina of various species, a strong downregulation of Kir4.1 protein expression as well as a reduction of amplitudes of potassium currents have been shown [8,9,10,11] In addition to their role in ion homeostasis, Kir4.1 channels are involved in the maintenance of the negative membrane potential of Muller cells as well as of other glial cells [4]. Possible associations between polymorphisms of the gene for aquaporin-4 and epilepsy have been described [19] Glial cells such as retinal Muller glial cells are involved in potassium ion and water homeostasis of the neural tissue. Laminins in the extracellular matrix, dystroglycan in the membrane, and dystrophins in the cytomatrix form a complex mediating the polarized expression of Kir4.1 and aquaporin-4 in Muller cells
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