Ancient medicinal plant rosemary contains a highly efficacious and isoform-selective KCNQ potassium channel opener.

Autor: Manville RW; Bioelectricity Laboratory, Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA., Hogenkamp D; Bioelectricity Laboratory, Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA., Abbott GW; Bioelectricity Laboratory, Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA. abbottg@hs.uci.edu.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Jun 15; Vol. 6 (1), pp. 644. Date of Electronic Publication: 2023 Jun 15.
DOI: 10.1038/s42003-023-05021-8
Abstrakt: Voltage-gated potassium (Kv) channels in the KCNQ subfamily serve essential roles in the nervous system, heart, muscle and epithelia. Different heteromeric KCNQ complexes likely serve distinct functions in the brain but heteromer subtype-specific small molecules for research or therapy are lacking. Rosemary (Salvia rosmarinus) is an evergreen plant used medicinally for millennia for neurological and other disorders. Here, we report that rosemary extract is a highly efficacious opener of heteromeric KCNQ3/5 channels, with weak effects on KCNQ2/3. Using functional screening we find that carnosic acid, a phenolic diterpene from rosemary, is a potent, highly efficacious, PIP 2 depletion-resistant KCNQ3 opener with lesser effects on KCNQ5 and none on KCNQ1 or KCNQ2. Carnosic acid is also highly selective for KCNQ3/5 over KCNQ2/3 heteromers. Medicinal chemistry, in silico docking, and mutagenesis reveal that carboxylate-guanidinium ionic bonding with an S4-5 linker arginine underlies the KCNQ3 opening proficiency of carnosic acid, the effects of which on KCNQ3/5 suggest unique therapeutic potential and a molecular basis for ancient neurotherapeutic use of rosemary.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje