Hyperforin activates nonselective cation channels (NSCCs)
Article first published online: 29 JAN 2009
2005 British Pharmacological Society
British Journal of Pharmacology
Volume 145, Issue 1, pages 75–83, May 2005
How to Cite
Treiber, K., Singer, A., Henke, B. and Müller, W. E. (2005), Hyperforin activates nonselective cation channels (NSCCs). British Journal of Pharmacology, 145: 75–83. doi: 10.1038/sj.bjp.0706155
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received September 29, 2004, Revised November 25, 2004, Accepted December 21, 2004)
- St John's wort;
- TRPC channels;
- SK&F 96365;
- LOE 908;
- 1A large body of evidence supports the preclinical antidepressant profile of hyperforin including inhibition of the synaptosomal uptake of several neurotransmitters by hyperforin and studies in behavioural models. In contrast to other antidepressants, hyperforin does not directly inhibit neurotransmitter transporters, but instead uptake inhibition seems to be the consequence of an elevated intracellular sodium concentration ([Na+]i).
- 2The mechanism of hyperforin-induced elevation of [Na+]i was investigated using two different cell types: human platelets and rat pheochromocytoma cells (PC12 cells). In both cell systems, hyperforin increased both [Na+]i and free intracellular Ca2+ concentration ([Ca2+]i).
- 3One pathway for Na+ and Ca2+ entry is mediated by nonselective cation channels (NSCCs), which can be blocked by SK&F 96365 and LOE 908. LOE 908 is a blocker of both NSCC1 and NSCC2 subclasses, while SK&F 96365 blocks NSCC2 only. Both SK&F 96365 and LOE 908 completely inhibited the hyperforin-induced influx of Na+ and Ca2+ into platelets and PC12 cells. This indicates that hyperforin is mainly active upon NSCC2.
- 4The effect of hyperforin is inhibited by La3+ and Gd3+, indicating that there is a potential homology with canonical transient receptor potential protein channels (TRPC channels). Moreover, La3+ and Gd3+ attenuate the effect of hyperforin on serotonin uptake in human platelets. Additionally, hyperforin induces barium influx in PC12 cells and this influx can be inhibited by SK&F 96365, LOE 908, Gd3+ and La3+.
- 5In summary, these findings suggest that hyperforin represents a new principle for preclinical antidepressant activity, modulating brain neurotransmission by inhibition of neurotransmitter uptake via activation of NSCCs.
British Journal of Pharmacology (2005) 145, 75–83. doi:10.1038/sj.bjp.0706155