Hyperforin activates TRP channels via tyrosine kinases
The preclinical antidepressant profile of Hyperforin is supported by a large body of evidence. Hyperforin is active in many relevant behavioral models, alters brain levels of serotonin, norepinephrine, dopamine and inhibits synaptosomal uptake of all three neurotransmitters in vivo. In contrast to classical antidepressants, Hyperforin does not directly interact with the transporter molecules. Therefore, we suggested that re-uptake inhibition might be the consequence of an elevation of the intracellular sodium concentration, as the re-uptake of all neurotransmitters is strongly depending on the sodium gradient. We have previously shown that Hyperforin elevates the intracellular sodium concentration by activating TRPC channels in PC12 cells (Treiber et al., 2005). Furthermore we were able to show, that TRP channel blockers attenuated the Hyperforin-induced inhibition of specific serotonin uptake into human platelets. We now address the question whether Hyperforin directly activates TRPC channels or if signal transduction pathways are involved. In mammalian cells TRPC channels are activated primarily by tyrosine kinase (TK) receptors via phospholipase C γ (PLCgγ). PC12 cells were preincubated with different TK inhibitors and PLC blockers and afterwards stimulated with Hyperforin. All blockers inhibited the Hyperforin induced non selective cation influx. Therefore, we propose that Hyperforin mediates its antidepressant activity by activating TRPC channels via TK and PLC.
This work was supported by the DFG and Dr. W. Schwabe