Conifer metabolite pisiferic acid restores activity in human Kv1.2 potassium channels carrying pathogenic sequence variants

Sequence variants in KCNA2, the gene encoding voltage-gated potassium
channel Kv1.2, cause epilepsy, intellectual disability, and movement
disorders. Drugs that directly correct mutant Kv1.2 function are lacking.
 Kv1.2 downregulation is also implicated in pain and amyotrophic
lateral sclerosis (ALS). We recently found that the abietane diterpenoid
pisiferic acid (PA) from conifer Chamaecyparis pisifera beneficially
restores activity in pathogenic loss-of-function (LOF)-variant Kv1.1
channels.  Here, using cellular electrophysiology, we classified
19 human Kv1.2 gene variants (pathogenic or of unknown significance) into
LOF, gain of function (GOF), or mixed LOF/GOF. By hyperpolarizing their
voltage dependence of activation, PA improved function in 13/13 LOF and
1/1 LOF/GOF pathogenic Kv1.2 variants tested, using cRNA ratios
representative of autosomal dominant KCNA2 disorders. In silico docking,
mutagenesis, and electrophysiology identified a PA binding site in the
Kv1.2 voltage sensor.  Given its in vitro efficacy and low
preclinical toxicity, PA is a promising lead compound for Kv1.2 LOF
disorders.