Hyperforin—a key constituent of St. John's wort specifically activates TRPC6 channels

Abstract

Hyperforin, a bicyclic polyprenylated acylphloroglucinol derivative, is the main active principle of St. John's wort extract responsible for its anti‐depressive profile. Hyperforin inhibits the neuronal serotonin and norepinephrine uptake comparable to synthetic antidepressants. In contrast to synthetic anti‐depressants directly blocking neuronal amine uptake, hyperforin increases synaptic serotonin and norepi‐nephrine concentrations by an indirect and yet unknown mechanism. Our attempts to identify the molecular target of hyperforin resulted in the identification of TRPC6. Hyperforin induced sodium and calcium entry as well as currents in TRPC6‐expressing cells. Sodium currents and the subsequent breakdown of the membrane sodium gradients may be the rationale for the inhibition of neuronal amine uptake. The hyper‐forin‐induced cation entry was highly specific and related to TRPC6 and was suppressed in cells expressing a dominant negative mutant of TRPC6, whereas phylo‐genetically related channels, i.e., TRPC3 remained unaffected. Furthermore, hyperforin induces neuronal axonal sprouting like nerve growth factor in a TRPC6‐dependent manner. These findings support the role of TRPC channels in neurite extension and identify hyper‐forin as the first selective pharmacological tool to study TRPC6 function. Hyperforin integrates inhibition of neurotransmitter uptake and neurotrophic property by specific activation of TRPC6 and represents an interesting lead‐structure for a new class of antidepres‐sants.— Leuner, K., Kazanski, V., Müller, M., Essin, K., Henke, B., Gollasch, M., Harteneck, C., Müller, W. E. Hyperforin—a key constituent of St. John's wort specifically activates TRPC6 channels. FASEB J . 21, 4101–4111 (2007)