Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis.
Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM)1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release.
Department of Neurology.
Yiguo
Y
Shen
Department of Physiology, and.
Woo-Ping
WP
Ge
Department of Cellular & Molecular Physiology, Stanford University, Palo Alto, CA 94304; and.
Yulong
Y
Li
Department of Neurology.
Arisa
A
Hirano
Department of Neurology.
Hsien-Yang
HY
Lee
Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University & Cluster of Excellence EXC 1003, Cells in Motion, D-48149 Münster, Germany.
Astrid
A
Rohlmann
Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University & Cluster of Excellence EXC 1003, Cells in Motion, D-48149 Münster, Germany.
Markus
M
Missler
Department of Cellular & Molecular Physiology, Stanford University, Palo Alto, CA 94304; and.
Richard W
RW
Tsien
Department of Physiology, and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158;
Lily Yeh
LY
Jan
Department of Neurology, ying-hui.fu@ucsf.edu ljp@ucsf.edu.
Ying-Hui
YH
Fu
Department of Neurology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94158; ying-hui.fu@ucsf.edu ljp@ucsf.edu.
Louis J
LJ
Ptáček
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002819:Chorea / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D013572:Synaptic Vesicles / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse; D009124:Muscle Proteins; C547209:myofibrillogenesis regulator-1, mouse
exocytosis; neurological disease; paroxysmal dyskinesia