Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 46, Pages 29090-29100Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2001177117
Keywords
GPCR signaling; TRP channels; alternative splicing; opioid analgesia
Categories
Funding
- European Research Council (ERC) under European Union Horizon 2020 Framework Program ERC [647458]
- Flanders Institute for Biotechnology (VIB) [C0401]
- Industrial Research Fund of KU Leuven (Industrieel Onderzoeksfonds)
- Funds for Scientific Research Flanders (FWO
- Hercules Foundation grant) [AKUL/15/34 -G0H1716N]
- Flanders Agency for Innovation by Science and Technology (IWT
- SBO grant) [60839]
- KU Leuven [RUN/16/001, ZKD4582 C16/18/008, 30550343, C14/17/093]
- FWO [G0C6814N]
- Fund for Scientific Research Flanders Postdoctoral Fellowship [FWO 12P0919N, FWO 12W4618N]
- NIH [R01 NS055159, R01 GM093290]
- HOMFOR grant from Universitat Saarbrucken
- FWO-Vlaanderen research project [G0C9717N]
- DFG program [SFB 593]
- European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie Grant [665501]
- research Foundation Flanders (FWO-Vlaanderen)
Ask authors/readers for more resources
TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by mu-opioid receptors through the signaling of G beta gamma proteins, thereby reducing TRPM3-mediated pain. We show here that G beta gamma directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with G beta gamma. Using these data and mutational analysis of full-length proteins, we pinpoint three amino acids in TRPM3 and their interacting partners in G beta 1 that are indi-vidually necessary for TRPM3 inhibition by G beta gamma. The 10-amino-acid G beta gamma-interacting domain in TRPM3 is subject to alternative splicing. Its inclusion in or exclusion from TRPM3 channel proteins therefore provides a mechanism for switching on or off the inhibitory action that G beta gamma proteins exert on TRPM3 channels.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available