Human Molecular Genetics Advance Access originally published online on March 6, 2007
Human Molecular Genetics 2007 16(9):1017-1029; doi:10.1093/hmg/ddm047
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Mpp4 is required for proper localization of plasma membrane calcium ATPases and maintenance of calcium homeostasis at the rod photoreceptor synaptic terminals
1 The Berman-Gund Laboratory for the Study of Retinal Degenerations and 2 The Howe Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA
* To whom correspondence should be addressed at: Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114, USA. Tel: +1 6175733904; Fax: +1 6175733216; Email: tli{at}meei.harvard.edu
Received January 22, 2007; Accepted February 26, 2007
Membrane palmitoylated protein 4 (Mpp4) is a member of the membrane-associated guanylate kinase family. We show that Mpp4 localizes specifically to the plasma membrane of photoreceptor synaptic terminals. 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 were lost from rod photoreceptor presynaptic membranes. Synaptic ribbons were enlarged, a phenomenon known to correlate with higher Ca2+. SERCA2 (sarcoplasmic-endoplasmic reticulum Ca2+ ATPase, type 2), which pumps cytosolic Ca2+ into intracellular Ca2+ stores and localizes next to the ribbons, was increased. The distribution of IP3RII (InsP3 receptor, type 2), which releases Ca2+ from the stores, was shifted away from the synaptic terminals. Synaptic transmission to second-order neurons was maintained but was reduced in amplitude. These data suggest that loss of Mpp4 disrupts a Ca2+ extrusion mechanism at the presynaptic membranes, with ensuing adaptive responses by the photoreceptor to restore Ca2+ homeostasis. We propose that Mpp4 organizes a presynaptic protein complex that includes PMCAs and has a role in modulating Ca2+ homeostasis and synaptic transmission in rod photoreceptors.
Present address: Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
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