Mpp4 is required for proper localization of plasma membrane calcium ATPases and maintenance of calcium homeostasis at the rod photoreceptor synaptic terminals.
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 Ca(2+) ATPases (PMCAs), the Ca(2+) 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 Ca(2+). SERCA2 (sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase, type 2), which pumps cytosolic Ca(2+) into intracellular Ca(2+) stores and localizes next to the ribbons, was increased. The distribution of IP(3)RII (InsP(3) receptor, type 2), which releases Ca(2+) 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 Ca(2+) extrusion mechanism at the presynaptic membranes, with ensuing adaptive responses by the photoreceptor to restore Ca(2+) homeostasis. We propose that Mpp4 organizes a presynaptic protein complex that includes PMCAs and has a role in modulating Ca(2+) homeostasis and synaptic transmission in rod photoreceptors.
Pubmed ID: 17341488 RIS Download
Adaptor Proteins, Signal Transducing | Animals | Calcium | Fluorescent Antibody Technique | Gene Deletion | Guanylate Kinases | Homeostasis | Intracellular Signaling Peptides and Proteins | Membrane Proteins | Mice | Mice, Knockout | Microscopy, Confocal | Microscopy, Electron, Transmission | Microscopy, Immunoelectron | Models, Biological | Multiprotein Complexes | Plasma Membrane Calcium-Transporting ATPases | Presynaptic Terminals | Protein Binding | Retinal Rod Photoreceptor Cells | Synaptic Transmission | Two-Hybrid System Techniques