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.
Yang
Jun
J
The Berman-Gund Laboratory for Study of Retinal Degenerations, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
Pawlyk
Basil
B
Wen
Xiao-Hong
XH
Adamian
Michael
M
Soloviev
Maria
M
Michaud
Norman
N
Zhao
Yun
Y
Sandberg
Michael A
MA
Makino
Clint L
CL
Li
Tiansen
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D051528:Guanylate Kinases; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D016253:Microscopy, Immunoelectron; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C114672:Lin7c protein, mouse; D008565:Membrane Proteins; C477071:Mpp4 protein, mouse; D046912:Multiprotein Complexes; D051528:Guanylate Kinases; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium