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J. Yang, B. Pawlyk, X.-H. Wen, M. Adamian, Y. Zhao, M. A. Sandberg, C. L. Makino, T. Li; Mpp4 at the Photoreceptor Synaptic Terminals: Anchoring Plasma Membrane Calcium ATPases and Modulating Calcium Homeostasis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3069.
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© ARVO (1962-2015); The Authors (2016-present)
Membrane palmitoylated protein 4 (Mpp4) is a photoreceptor-specific protein belonging to the membrane-associated guanylate kinase family, with unknown biological functions. We carried out genetic, cell biological and biochemical studies to define the function of Mpp4 in photoreceptor cells.
The Mpp4 gene was disrupted by gene targeting in mice. Phenotype analysis and protein functional studies utilized light and electron microscopy, immunofluorescence, Western blotting, immunoprecipitation, yeast two-hybrid protein interaction analysis, electroretinography (ERG), and single cell recordings.
Mpp4 localizes specifically to the synaptic terminals of both rod and cone photoreceptors. Plasma membrane Ca2+ ATPases (PMCAs), the Ca2+ extrusion pumps, interact with an Mpp4-dependent presynaptic membrane protein complex that includes Veli3 and PSD95. In mice lacking Mpp4, PMCAs are lost from the photoreceptor pre-synaptic membranes. Synaptic ribbons are enlarged. Sarcoplasmic-endoplasmic reticulum Ca2+ ATPase, type 2, localizing close to the ribbons, is increased. The distribution of InsP3 receptor, type 2 shifts from the synaptic terminal to the basal outer segment. Although single cell recordings show largely intact phototransduction, delays in the timing and reduced amplitudes of ERG b-waves and oscillatory potentials indicate that synaptic transmission to second-order retinal neurons is abnormal.
Loss of Mpp4 disrupts a major Ca2+ extrusion mechanism at the presynaptic membranes, with ensuing adaptive responses by the photoreceptor cell to restore Ca2+ homeostasis. We conclude that Mpp4 affects Ca2+ homeostasis and modulates synaptic transmission in photoreceptors by organizing a presynaptic membrane protein complex that includes PMCAs.
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