The central focus of this renewal will be on the molecular understanding of the macromolecular organization and functions of glial potassium, bicarbonate and water transport proteins in the mammalian retina. How transport proteins work together to coordinate the transport of solutes and water across glial cell membranes is a fundamental question in neurobiology and retinal physiology. In the preceding period, we have identified the critical role of Kir4.1 channels in the regulation of extracellular potassium concentration in the retina. This study consists of a series of steps aimed to further elucidate the composition, architecture and functions of water channels (AQP4), potassium channels (Kir4.1) and sodium bicarbonate cotransporters in retinal glia.
The specific aims are the following: 1) to verify the hypothesis that potassium and water channels associate with the dystrophin glycoprotein complex (DGC) in Muller cell membranes, 2) to test the hypothesis that extracellular ligand signaling to the DGC is crucial for the highly localized expression of potassium and water channels in Muller cells, 3) determine the molecular identity of sodium bicarbonate cotransporter systems in Muller cells and verify whether they associate with the DGC, 4) extend our studies of the function of Kir4.1 channels to the retinal and optic nerve astrocytes. Potassium and water channels and sodium bicarbonate cotransporters play a critical role in potassium and acid-base buffering in retina and defects in their subunit assembly and macromolecular organization may be implicated in human diseases. The molecular understanding of the events that are central to their regulated expression is therefore essential for developing our knowledge in the area of retinal function in health and in diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Greenwell, Thomas
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Sand, Andrea; Schmidt, Tiffany M; Kofuji, Paulo (2012) Diverse types of ganglion cell photoreceptors in the mammalian retina. Prog Retin Eye Res 31:287-302
Schmidt, Tiffany M; Kofuji, Paulo (2011) An isolated retinal preparation to record light response from genetically labeled retinal ganglion cells. J Vis Exp :
Schmidt, Tiffany M; Do, Michael Tri H; Dacey, Dennis et al. (2011) Melanopsin-positive intrinsically photosensitive retinal ganglion cells: from form to function. J Neurosci 31:16094-101
Schmidt, Tiffany M; Kofuji, Paulo (2011) Structure and function of bistratified intrinsically photosensitive retinal ganglion cells in the mouse. J Comp Neurol 519:1492-504
Tang, X; Schmidt, T M; Perez-Leighton, C E et al. (2010) Inwardly rectifying potassium channel Kir4.1 is responsible for the native inward potassium conductance of satellite glial cells in sensory ganglia. Neuroscience 166:397-407
Schmidt, Tiffany M; Kofuji, Paulo (2010) Differential cone pathway influence on intrinsically photosensitive retinal ganglion cell subtypes. J Neurosci 30:16262-71
Tang, Xiaofang; Hang, Darwin; Sand, Andrea et al. (2010) Variable loss of Kir4.1 channel function in SeSAME syndrome mutations. Biochem Biophys Res Commun 399:537-41
Clark 3rd, J P; Kofuji, P (2010) Stoichiometry of N-methyl-D-aspartate receptors within the suprachiasmatic nucleus. J Neurophysiol 103:3448-64
Schmidt, Tiffany M; Kofuji, Paulo (2009) Functional and morphological differences among intrinsically photosensitive retinal ganglion cells. J Neurosci 29:476-82
Tang, Xiaofang; Taniguchi, Kenichiro; Kofuji, Paulo (2009) Heterogeneity of Kir4.1 channel expression in glia revealed by mouse transgenesis. Glia 57:1706-15

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