Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons

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Abstract

Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in organ development, brain function and govern immunological responses. Correspondingly, this receptor family is linked to a multitude of diverse human diseases. aGPCRs have been suggested to possess mechanosensory properties, though their mechanism of action is fully unknown. Here we show that the Drosophila aGPCR Latrophilin/dCIRL acts in mechanosensory neurons by modulating ionotropic receptor currents, the initiating step of cellular mechanosensation. This process depends on the length of the extended ectodomain and the tethered agonist of the receptor, but not on its autoproteolysis, a characteristic biochemical feature of the aGPCR family. Intracellularly, dCIRL quenches cAMP levels upon mechanical activation thereby specifically increasing the mechanosensitivity of neurons. These results provide direct evidence that the aGPCR dCIRL acts as a molecular sensor and signal transducer that detects and converts mechanical stimuli into a metabotropic response.

DOI: http://dx.doi.org/10.7554/eLife.28360.001

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Sanjeev S Ranade, Ruhma Syeda, Ardem Patapoutian (2015)

Mechanotransduction, the conversion of physical forces into biochemical signals, is essential for various physiological processes such as the conscious sensations of touch and hearing, and the unconscious sensation of blood flow. Mechanically activated (MA) ion channels have been proposed as sensors of physical force, but the identity of these channels and an understanding of how mechanical force is transduced has remained elusive. A number of recent studies on previously known ion channels along with the identification of novel MA ion channels have greatly transformed our understanding of touch and hearing in both vertebrates and invertebrates. Here, we present an updated review of eukaryotic ion channel families that have been implicated in mechanotransduction processes and evaluate the qualifications of the candidate genes according to specified criteria. We then discuss the proposed gating models for MA ion channels and highlight recent structural studies of mechanosensitive potassium channels.

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Author and article information

Contributors

Hugo J Bellen: Role: Reviewing editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 08 August 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: e28360

Affiliations

[1 ]deptDepartment of Neurophysiology, Institute of Physiology , University of Würzburg , Würzburg, Germany

[2 ]deptRudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty , Leipzig University , Leipzig, Germany

[3 ]deptInstitute of Pharmacology and Toxicology , University of Würzburg , Würzburg, Germany

[4 ]deptRudolf Virchow Center, DFG-Research Center for Experimental Biomedicine , University of Würzburg , Würzburg, Germany

[5 ]deptDepartment of Biology, Institute for Molecular Plant Physiology and Biophysics , University of Würzburg Biocenter , Würzburg, Germany

[6 ]deptDepartment of Biotechnology and Biophysics , University of Würzburg Biocenter , Würzburg, Germany

[7 ]deptInstitute of Anatomy and Cell Biology , University of Würzburg , Würzburg, Germany

[8 ]deptCore Unit Peptide Technologies, Medical Faculty , Leipzig University , Leipzig, Germany

[9 ]deptRudolf Schönheimer Institute of Biochemistry, Division of Molecular Biochemistry, Medical Faculty , Leipzig University , Leipzig, Germany

Howard Hughes Medical Institute, Baylor College of Medicine , United States

Author notes

tobias.langenhan@ 123456gmail.com (TL);

robert.kittel@ 123456uni-wuerzburg.de (RJK)

[†]

These authors contributed equally to this work.

Author information

Tobias Langenhan http://orcid.org/0000-0002-9061-3809

Robert J Kittel http://orcid.org/0000-0002-9199-4826

Article

Publisher ID: 28360

DOI: 10.7554/eLife.28360

PMC ID: 5548486

PubMed ID: 28784204

SO-VID: c246263f-1739-4a5b-88bd-0f46176e2887

License:

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