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Naunyn Schmiedebergs Arch Pharmacol. 2018 May 8. doi: 10.1007/s00210-018-1507-3. [Epub ahead of print]

Molecular basis for the sensitivity of TRP channels to polyunsaturated fatty acids.

Author information

1
Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA), Wilhelmstrasse 56, 72074, Tübingen, Germany.
2
Experimental and Clinical Research Center (ECRC), a joint cooperation of the Charité University Medicine and Max Delbruck Center for Molecular Medicine in the Helmholtz Association, Lindenberger Weg 80, 13125, Berlin, Germany.
3
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Berlin, Germany.
4
Structural Bioinformatics Group, Institute for Physiology, Charité - University Medicine Berlin, Berlin, Germany.
5
Experimental and Clinical Research Center (ECRC), a joint cooperation of the Charité University Medicine and Max Delbruck Center for Molecular Medicine in the Helmholtz Association, Lindenberger Weg 80, 13125, Berlin, Germany. maik.gollasch@charite.de.
6
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Berlin, Germany. maik.gollasch@charite.de.
7
Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA), Wilhelmstrasse 56, 72074, Tübingen, Germany. bernd.nuernberg@uni-tuebingen.de.

Abstract

Transient receptor potential (TRP) channels represent a superfamily of unselective cation channels that are subdivided into seven subfamilies based on their sequence homology and differences in gating and functional properties. Little is known about the molecular mechanisms of TRP channel regulation, particularly of the "canonical" TRP (TRPC) subfamily and their activation by polyunsaturated fatty acids (PUFAs). Here, we analyzed the structure-function relationship of Drosophila fruit fly TRPC channels. The primary aim was to uncover the molecular basis of PUFA sensitivity of Drosophila TRP-like (TRPL) and TRPgamma channels. Amino acid (aa) sequence alignment of the three Drosophila TRPC channels revealed 50 aa residues highly conserved in PUFA-sensitive TRPL and TRPgamma channels but not in the PUFA-insensitive TRP channel. Substitution of respective aa in TRPL by corresponding aa of TRP identified 18 residues that are necessary for PUFA-mediated activation of TRPL. Most aa positions are located within a stretch comprising transmembrane domains S2-S4, whereas six aa positions have been assigned to the proximal cytosolic C-terminus. Interestingly, residues I465 and S471 are required for activation by 5,8,11,14-eicosatetraynoic acid (ETYA) but not 5,8,11-eicosatriynoic acid (ETI). As proof of concept, we generated a PUFA-sensitive TRP channel by exchanging the corresponding aa from TRPL to TRP. Our study demonstrates a specific aa pattern in the transmembrane domains S2-S4 and the proximal C-terminus essential for TRP channel activation by PUFAs.

KEYWORDS:

Ca2+ influx; Drosophila; Polyunsaturated fatty acids; TRP channels; TRPC channels

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