Hyperforin activates nonselective cation channels (NSCCs).
A 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). The 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). One 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. The 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+. In 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.
Treiber
Kristina
K
Department of Pharmacology, Biocenter, N260, University of Frankfurt, Marie-Curie-Str. 9, 60439 Frankfurt, Germany.
Singer
Andrea
A
Henke
Bettina
B
Müller
Walter E
WE
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*
D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D007473:Ion Channels; D010696:Phloroglucinol; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D019831:Sodium-Calcium Exchanger; D013729:Terpenes; C001654:hyperforin
Br J Pharmacol. 2002 Aug;136(7):1015-22
12145101
J Pharmacol Exp Ther. 2002 May;301(2):714-9
11961077
J Neurosci. 2002 Nov 1;22(21):9453-64
12417670
Psychopharmacology (Berl). 2002 Dec;164(4):423-8
12457273
J Biol Chem. 2003 Feb 7;278(6):3562-71
12456670
Life Sci. 2003 Jun 13;73(4):461-70
12759140
Pharmacopsychiatry. 2001 Jul;34 Suppl 1:S148-51
11518066
J Neurosci. 2003 Jul 16;23(15):6215-22
12867505
Biochem Pharmacol. 2003 Dec 1;66(11):2177-84
14609742
Nature. 2003 Dec 4;426(6966):517-24
14654832
Br J Pharmacol. 2004 Jun;142(3):414-8
15148244
Annu Rev Biochem. 1983;52:871-926
6137190
J Biol Chem. 1985 Mar 25;260(6):3440-50
3838314
J Biol Chem. 1989 Nov 15;264(32):19458-67
2478559
FEBS Lett. 1990 Jul 30;268(1):79-82
1696554
Biochem J. 1990 Oct 15;271(2):515-22
2173565
J Physiol. 1991 Sep;441:559-73
1816386
Biochem J. 1992 Dec 15;288 ( Pt 3):1025-35
1281979
Biochim Biophys Acta. 1993 Apr 16;1176(3):215-21
8471623
Biochem J. 1994 Aug 15;302 ( Pt 1):187-90
8068004
Pflugers Arch. 1994 Oct;428(5-6):433-8
7838664
Br J Pharmacol. 1994 Nov;113(3):861-8
7858878
Cardiovasc Res. 1995 Feb;29(2):260-8
7736504
J Physiol. 1995 Jun 1;485 ( Pt 2):349-64
7666363
J Biol Chem. 1998 Jan 2;273(1):133-42
9417057
Biochem Biophys Res Commun. 1998 Jan 6;242(1):191-6
9439634
Life Sci. 1998;63(6):499-510
9718074
Biochem J. 1999 Jan 15;337 ( Pt 2):153-69
9882611
Neurosci Lett. 1999 Mar 12;262(3):199-202
10218890
J Pharmacol Exp Ther. 1999 Sep;290(3):1363-8
10454515
Neuropsychopharmacology. 2000 Aug;23(2):188-97
10882845
Circ Res. 2001 Feb 16;88(3):325-32
11179201
Life Sci. 2001 Feb 23;68(14):1593-605
11263672
J Biol Chem. 2001 Apr 20;276(16):13331-9
11278449
Trends Pharmacol Sci. 2001 Jun;22(6):292-7
11395157
Pharmacopsychiatry. 2001 Jul;34 Suppl 1:S61-9
11518079
Pharmacopsychiatry. 2001 Jul;34 Suppl 1:S89-97
11518084
Pharmacopsychiatry. 2001 Jul;34 Suppl 1:S103-7
11518055
Pharmacopsychiatry. 2001 Jul;34 Suppl 1:S111-5
11518058
Biochem J. 2001 Sep 15;358(Pt 3):717-26
11535132
Blood. 2002 Oct 15;100(8):2801-11
12351388