A Discrete Presynaptic Vesicle Cycle for Neuromodulator Receptors

Damien Jullié, Miriam Stoeber, Jean-Baptiste Sibarita, Hanna L. Zieger, Thomas M. Bartol, Seksiri Arttamangkul, Terrence J. Sejnowski, Eric Hosy, Mark von Zastrow
Neuron. 2020-02-01; 105(4): 663-677.e8
DOI: 10.1016/j.neuron.2019.11.016

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Jullié D(1), Stoeber M(2), Sibarita JB(3), Zieger HL(3), Bartol TM(4), Arttamangkul S(5), Sejnowski TJ(4), Hosy E(3), von Zastrow M(6).

Author information:
(1)Department of Cellular and Molecular Pharmacology, University of California,
San Francisco School of Medicine, San Francisco, CA 94158, USA; Department of
Psychiatry, University of California, San Francisco School of Medicine, San
Francisco, CA 94158, USA.
(2)Department of Cellular and Molecular Pharmacology, University of California,
San Francisco School of Medicine, San Francisco, CA 94158, USA; Department of
Psychiatry, University of California, San Francisco School of Medicine, San
Francisco, CA 94158, USA; Department of Cell Physiology and Metabolism,
University of Geneva, 1211 Geneva, Switzerland.
(3)Interdisciplinary Institute for Neuroscience, UMR 5297, Centre National de la
Recherche Scientifique, 33077 Bordeaux, France; Interdisciplinary Institute for
Neuroscience, University of Bordeaux, 33077 Bordeaux, France.
(4)Howard Hughes Medical Institute, Salk Institute for Biological Studies, La
Jolla, CA 92037, USA.
(5)The Vollum Institute, Oregon Health and Science University, Portland, OR
97239, USA.
(6)Department of Cellular and Molecular Pharmacology, University of California,
San Francisco School of Medicine, San Francisco, CA 94158, USA; Department of
Psychiatry, University of California, San Francisco School of Medicine, San
Francisco, CA 94158, USA. Electronic address: .

A major function of GPCRs is to inhibit presynaptic neurotransmitter release,
requiring ligand-activated receptors to couple locally to effectors at
terminals. The current understanding of how this is achieved is through receptor
immobilization on the terminal surface. Here, we show that opioid peptide
receptors, GPCRs that mediate highly sensitive presynaptic inhibition, are
instead dynamic in axons. Opioid receptors diffuse rapidly throughout the axon
surface and internalize after ligand-induced activation specifically at
presynaptic terminals. We delineate a parallel regulated endocytic cycle for
GPCRs operating at the presynapse, separately from the synaptic vesicle cycle,
which clears activated receptors from the surface of terminals and locally
reinserts them to maintain the diffusible surface pool. We propose an alternate
strategy for achieving local control of presynaptic effectors that, opposite to
using receptor immobilization and enforced proximity, is based on lateral
mobility of receptors and leverages the inherent allostery of GPCR-effector
coupling.

Copyright © 2019 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.neuron.2019.11.016
PMCID: PMC7035187
PMID: 31837915 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Interests The authors declare no
competing interests.

Auteurs Bordeaux Neurocampus