title: The active-zone protein Munc13 controls the use-dependence of presynaptic voltage-gated calcium channels.
abstract: Presynaptic calcium channel function is critical for converting electrical information into chemical communication but the molecules in the active zone that sculpt this function are poorly understood. We show that Munc13, an active-zone protein essential for exocytosis, also controls presynaptic voltage-gated calcium channel (VGCC) function dictating their behavior during various forms of activity. We demonstrate that in vitro Munc13 interacts with voltage-VGCCs via a pair of basic residues in Munc13's C2B domain. We show that elimination of this interaction by either removal of Munc13 or replacement of Munc13 with a Munc13 C2B mutant alters synaptic VGCC's response to and recovery from high-frequency action potential bursts and alters calcium influx from single action potential stimuli. These studies illustrate a novel form of synaptic modulation and show that Munc13 is poised to profoundly impact information transfer at nerve terminals by controlling both vesicle priming and the trigger for exocytosis.
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, United States.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Calloway
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, United States.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Gouzer
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, United States.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Ryan
mesh_terms: D000200:Action Potentials; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000502:physiology*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D009419:Nerve Tissue Proteins; C103912:Unc13a protein, rat
keywords: Munc13; calcium channels; neuroscience; plasticity; rat