Hyperforin mediates neurite outgrowth via TRPC6 channels in PC12 cells

Hyperforin, a bicyclic polyprenylated acylphloroglucinol derivative, is the main active principle of St. John's wort extract responsible for its antidepressive profile. Hyperforin inhibits the neuronal uptake of serotonin and norepinephrine comparable to synthetic antidepressants. Whereas synthetic antidepressants directly block neuronal amine uptake, hyperforin increases synaptic serotonin and norepinephrine concentrations by an indirect and yet unknown mechanism. We identified TRPC6 as the molecular target of hyperforin. The hyperforin-induced non-selective cation entry e.g. sodium and calcium was highly specific and related to TRPC6. Sodium currents and the subsequent breakdown of the membrane sodium gradients may be the rationale for the inhibition of neuronal amine uptake. In cells expressing a dominant negative mutant of TRPC6 or cells treated with anti-TRPC6 siRNA hyperforin induced calcium influx was strongly diminished. In addition, hyperforin induces neuronal axonal sprouting like NGF in a TRPC6-dependent manner. In cells transfected with anti-TRPC6 siRNA or cells expressing a dominant negative mutant of TRPC6 hyperforin induced neurite outgrowth was strongly reduced. These findings identify hyperforin as the first selective pharmacological tool to study TRPC6 function. Furthermore, hyperforin integrates two important pharmacological activities the inhibition of neurotransmitter uptake and neurotrophic properties by the unique and specific activation of TRPC6.