Fig 6. Schematic representation of BKαβ₁ channel’s role in tungstate-induced, G_i protein-mediated ERK phosphorylation and its interaction with PDGF-stimulated cell proliferation in human vascular smooth muscle.

PDGF stimulates both the Ras/Raf/MEK/ERK and the phosphatidylinositol 3-kinase (PI3K)/Akt mitogenic signaling pathways to induce vascular smooth muscle cell (VSMC) proliferation [35]. Tungstate (WO₄ ^2-) binding to the BK channel α subunit at a site involving residues of the Voltage Sensor Domain (silver circles in the S0–S1 and S2–S3 linkers) [14, 26] promotes activation of the voltage sensor and channel gating in a β₁ subunit-dependent manner, and subsequently, activation of PTX-sensitive G proteins to induce ERK phosphorylation and inhibition of PDGF-stimulated VSMC proliferation. Binding of iberiotoxin (IbTX) to the external mouth of the channel in close proximity to the β₁ extracellular loop, which plays an important role in the modulation of voltage sensor activation and gating of the BK channel [21, 46–53], may impair the conformational changes in the BKαβ₁ channel produced by tungstate to prevent the coupling of channel gating to G protein activation without the need of K⁺ conduction. For further details, please see Discussion.