Rosemary metabolite carnosic acid opens K _v 1.1 via its voltage sensor and corrects K _v 1.1‐linked episodic ataxia in mice

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 K v 1.1 ( KCNA1 ). Small molecules that restore K v 1.1 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 K v 1.1‐linked EA1 mutant channels. We assessed ataxia therapeutic efficacy by comparing performance of Kcna1 +/+ and Kcna1 E283K/+ 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 K v 1.1 openers. Carnosic acid fully or partially corrects heterozygous, heteromeric K v 1.1 EA1 mutant channel activity in vitro and restores normal function in K v 1.1 E283K/+ 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 K v 1.1. Finally, we determined the chemical properties that endow carnosic acid with the ability to open K v 1.1 channels. Conclusions and Implications Our findings uncover a K v 1.1 opener with the potential to reverse EA1 and other K v 1.1‐linked disorders.