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Rosemary metabolite carnosic acid opens Kv1.1 via its voltage sensor and corrects Kv1.1-linked episodic ataxia in
Rían W Manville1, Ryan F Yoshimura1, Hanh A Nguyen1
1Bioelectricity Laboratory, Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.
Background And Purpose:
Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder caused primarily by loss-of-function mutations in the voltage-gated potassium channel Kv1.1 (KCNA1). Small molecules that restore Kv1.1 activity hold promise as targeted therapies for EA1, yet current pharmacological strategies remain limited.
Experimental Approach:
Two electrode voltage-clamp electrophysiology and the Xenopus laevis oocyte expression system were used to study effects of carnosic acid, a phenolic diterpene from Salvia rosmarinus (rosemary) leaf extract on Kv1.1-linked EA1 mutant channels. We assessed ataxia therapeutic efficacy by comparing performance of Kcna1+/+ and Kcna1E283K/+ mice, a model of human EA1, on a balance beam under isoproterenol challenge in the absence or presence of 0.3-mg·kg-1 carnosic acid.
Key Results:
Rosemary leaf extract and rosemary metabolite carnosic acid are efficacious Kv1.1 openers. Carnosic acid fully or partially corrects heterozygous, heteromeric Kv1.1 EA1 mutant channel activity in vitro and restores normal function in Kv1.1E283K/+ mice at 0.3 mg·kg-1. Experimental validation of unbiased in silico docking reveals carnosic acid occupies a binding pocket between the S1 and S4 helices of the voltage-sensing domain (VSD) of Kv1.1. Finally, we determined the chemical properties that endow carnosic acid with the ability to open Kv1.1 channels.
Conclusions And Implications:
Our findings uncover a Kv1.1 opener with the potential to reverse EA1 and other Kv1.1-linked disorders.
