Hyperforin activates nonselective cation channels (NSCCs).

Area of Science:

• Pharmacology
• Neuroscience
• Cell Biology

Background:

• Hyperforin exhibits preclinical antidepressant properties by inhibiting neurotransmitter uptake.
• Unlike other antidepressants, hyperforin's mechanism involves elevated intracellular sodium concentration ([Na+]i), not direct transporter inhibition.

Purpose of the Study:

• To investigate the mechanism of hyperforin-induced elevation of intracellular sodium concentration ([Na+]i).
• To identify the ion channels involved in hyperforin's action on neurotransmitter uptake.

Main Methods:

• Utilized human platelets and rat pheochromocytoma (PC12) cells to study hyperforin's effects.
• Measured intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentrations.
• Investigated the role of nonselective cation channels (NSCCs) using blockers like SK&F 96365 and LOE 908, and lanthanides (La3+, Gd3+).

Main Results:

• Hyperforin increased both [Na+]i and intracellular calcium ([Ca2+]i) in both cell types.
• The influx of Na+ and Ca2+ induced by hyperforin was completely inhibited by NSCC blockers, indicating activation of NSCCs, particularly NSCC2.
• Lanthanides (La3+, Gd3+) inhibited hyperforin's effect on Na+ and Ca2+ influx and serotonin uptake, suggesting homology with TRPC channels.
• Hyperforin induced barium influx in PC12 cells, also inhibited by NSCC blockers and lanthanides.

Conclusions:

• Hyperforin activates nonselective cation channels (NSCCs), specifically NSCC2, leading to increased intracellular sodium and calcium.
• This activation modulates neurotransmitter uptake, representing a novel mechanism for preclinical antidepressant activity.
• The findings suggest hyperforin's potential as a new class of antidepressant by targeting NSCCs.