MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity

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Abstract

Presynaptic homeostatic plasticity (PHP) controls synaptic transmission in organisms from Drosophila to human and is hypothesized to be relevant to the cause of human disease. However, the underlying molecular mechanisms of PHP are just emerging and direct disease associations remain obscure. In a forward genetic screen for mutations that block PHP we identified mctp (Multiple C2 Domain Proteins with Two Transmembrane Regions). Here we show that MCTP localizes to the membranes of the endoplasmic reticulum (ER) that elaborate throughout the soma, dendrites, axon and presynaptic terminal. Then, we demonstrate that MCTP functions downstream of presynaptic calcium influx with separable activities to stabilize baseline transmission, short-term release dynamics and PHP. Notably, PHP specifically requires the calcium coordinating residues in each of the three C2 domains of MCTP. Thus, we propose MCTP as a novel, ER-localized calcium sensor and a source of calcium-dependent feedback for the homeostatic stabilization of neurotransmission.

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Özgür Genç

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Dion Kai Dickman

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-1884-284X
Wenpei Ma

Department of Biological Sciences, University of Southern California, Los Angeles, United States

Competing interests
No competing interests declared.
Amy Tong

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Richard D Fetter

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Graeme W Davis

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

For correspondence
graeme.davis@ucsf.edu

Competing interests
Graeme W Davis, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0003-1355-8401

Funding

National Institute of Neurological Disorders and Stroke (NS039313)

Graeme W Davis

National Institutes of Neurological Disorders and Stroke (NS097212)

Graeme W Davis

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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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.