Hyperforin--a key constituent of St. John's wort specifically activates TRPC6 channels.
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 serotonin and norepinephrine uptake comparable to synthetic antidepressants. In contrast to synthetic antidepressants directly blocking neuronal amine uptake, hyperforin increases synaptic serotonin and norepinephrine 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 hyperforin-induced cation entry was highly specific and related to TRPC6 and was suppressed in cells expressing a dominant negative mutant of TRPC6, whereas phylogenetically 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 hyperforin 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 antidepressants.
Pharmakologisches Institut für Naturwissenschaftler, Biocenter Niederursel, 60438 Frankfurt, Germany.
Kristina
K
Leuner
Victor
V
Kazanski
Margarethe
M
Müller
Kirill
K
Essin
Bettina
B
Henke
Maik
M
Gollasch
Christian
C
Harteneck
Walter E
WE
Müller
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020902:Hypericum / Q000737:chemistry* / Q000502:physiology*; D016716:PC12 Cells; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010936:Plant Extracts / Q000627:therapeutic use; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000037:antagonists & inhibitors / Q000378:metabolism; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013729:Terpenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D010936:Plant Extracts; D050052:TRPC Cation Channels; D013729:Terpenes; C492145:Trpc6 protein, rat; D012964:Sodium; D010696:Phloroglucinol; C001654:hyperforin; D002118:Calcium