The active-zone protein Munc13 controls the use-dependence of presynaptic voltage-gated calcium channels

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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 function dictating their behavior during various forms of activity. We demonstrate that in vitro Munc13 interacts with voltage-gated calcium channels 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.

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Nathaniel Calloway

Department of Biochemistry, Weill Cornell Medical College, New York, United States

Competing interests
The authors declare that no competing interests exist.
Géraldine Gouzer

Department of Biochemistry, Weill Cornell Medical College, New York, United States

Competing interests
The authors declare that no competing interests exist.
Mingyu Xue

Department of Biochemistry, Weill Cornell Medical College, New York, United States

Competing interests
The authors declare that no competing interests exist.
Timothy A Ryan

Department of Biochemistry, Weill Cornell Medical College, New York, United States

For correspondence
taryan@med.cornell.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (0601-450A) of Weill Cornell Medical College.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.