Cell Cycle Regulation by Ca²⁺-Activated K⁺ (BK) Channels Modulators in SH-SY5Y Neuroblastoma Cells

Area of Science:

• Neuroscience
• Pharmacology
• Cell Biology

Background:

• Calcium-activated potassium (BK) channels play crucial roles in cellular functions, including proliferation and cell cycle regulation.
• Dysregulation of BK channel activity is implicated in various pathological conditions.

Purpose of the Study:

• To investigate the effects of Paxilline (PAX), Iberiotoxin (IbTX), and Resveratrol (RESV) on BK channels in SH-SY5Y cells.
• To determine the impact of these modulators on cell proliferation, cell cycle, AKT1 phosphorylation, and cell morphology.

Main Methods:

• Utilized Operetta-high-content imaging, ELISA assays, impedentiometric counting, and patch-clamp electrophysiology.
• Investigated BK channel currents, cell proliferation, AKT1pSer473 phosphorylation, cell cycle progression, and cell diameter.

Main Results:

• PAX, IbTX, and RESV significantly reduced outward BK currents, leading to cell depolarization and calcium influx.
• All three compounds inhibited cell proliferation in a concentration-dependent manner, with significant reductions observed after 6 hours.
• PAX, IbTX, and RESV induced distinct but overlapping effects on cell cycle progression (G1, S, G2 phases) and reduced cell diameter.
• AKT1pSer473 dephosphorylation was observed, linked to calcium-dependent phosphatase activity.
• PAX exhibited potent antiproliferative effects, potentially enhanced by its action on nuclear membrane BK channels, leading to early apoptosis.

Conclusions:

• PAX, IbTX, and RESV act as BK channel blockers, inducing cell depolarization, calcium influx, AKT1pSer473 dephosphorylation, G2 cell cycle arrest, and reduced proliferation.
• These findings highlight the critical role of BK channels in regulating cell growth and suggest their potential as therapeutic targets.