The Intermediate-conductance Calcium-activated Potassium Channel KCa3.1 Regulates Vascular Smooth Muscle Cell Proliferation via Controlling Calcium-dependent Signaling.
The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to a variety of cell activation processes in pathologies such as inflammation, carcinogenesis and vascular remodeling. We examined the electrophysiological and transcriptional mechanisms by which KCa3.1 regulates vascular smooth muscle cell (VSMC) proliferation. Platelet-derived growth factor-BB (PDGF)-induced proliferation of human coronary artery VSMCs was attenuated by lowering intracellular Ca(2+) concentration ([Ca(2+)]i) and was enhanced by elevating [Ca(2+)]i. KCa3.1 blockade or knockdown inhibited proliferation by suppressing the rise in [Ca(2+)]i and attenuating the expression of phosphorylated cAMP response element binding protein (CREB), c-fos and neuron-derived orphan receptor-1 (NOR-1). This anti-proliferative effect was abolished by elevating [Ca(2+)]i. KCa3.1 overexpression induced VSMC proliferation, and potentiated PDGF-induced proliferation, by inducing CREB phosphorylation, c-fos and NOR-1. Pharmacological stimulation of KCa3.1 unexpectedly suppressed proliferation by inhibiting the rise in [Ca(2+)]i and abolishing the expression and activity of KCa3.1 and PDGF β-receptors. The stimulation also attenuated the levels of phosphorylated CREB, c-fos and cyclins expression. After KCa3.1 blockade, the characteristic round shape of VSMCs expressing high l-caldesmon and low calponin-1 (dedifferentiation state) was maintained, whereas KCa3.1 stimulation induced a spindle-shape cellular appearance, with low l-caldesmon and high calponin-1. In conclusion, KCa3.1 plays an important role in VSMC proliferation via controlling Ca(2+)-dependent signaling pathways and its modulation may therefore constitute a new therapeutic target for cell proliferative diseases such as atherosclerosis.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-N GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-N CHEMICAL GENE-N GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
Ca(2+) Calcium Calcium Potassium NOR-1 KCa3.1 KCa3.1 PDGF β-receptors phosphorylated CREB c-fos Ca(2+) cyclins KCa3.1 l-caldesmon calponin-1 KCa3.1 l-caldesmon calponin-1 KCa3.1 KCa3.1 Platelet-derived growth factor-BB Ca(2+) PDGF intermediate-conductance calcium-activated potassium channel KCa3.1 KCa3.1 phosphorylated cAMP response element binding protein CREB c-fos neuron-derived orphan receptor-1 NOR-1 KCa3.1 PDGF calcium CREB c-fos Intermediate-conductance Calcium-activated Potassium Channel KCa3.1 potassium Ca(2+) Ca(2+) Ca(2+) Ca(2+) cAMP