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Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):2935-41. doi: 10.1073/pnas.1501364112. Epub 2015 Feb 17.

Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis.

Author information

1
Department of Neurology.
2
Department of Physiology, and.
3
Department of Cellular & Molecular Physiology, Stanford University, Palo Alto, CA 94304; and.
4
Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University & Cluster of Excellence EXC 1003, Cells in Motion, D-48149 Münster, Germany.
5
Department of Physiology, and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158;
6
Department of Neurology, ying-hui.fu@ucsf.edu ljp@ucsf.edu.
7
Department of Neurology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94158; ying-hui.fu@ucsf.edu ljp@ucsf.edu.

Abstract

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.

KEYWORDS:

exocytosis; neurological disease; paroxysmal dyskinesia

PMID:
25730884
PMCID:
PMC4364199
DOI:
10.1073/pnas.1501364112
[Indexed for MEDLINE]
Free PMC Article

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