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

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 nervous system and other disorders.
Here, we discovered that rosemary extract is a highly efficacious opener
of heteromeric KCNQ3/5 channels, with weak effects on KCNQ2/3. Using
functional screening we found that carnosic acid, a phenolic diterpene
from rosemary, is a potent, highly efficacious, PIP2 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
revealed 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.