Faculty Collaboration Database

The intermediate conductance calcium-activated potassium channel KCa3.1 regulates vascular smooth muscle cell proliferation via controlling calcium-dependent signaling. J Biol Chem 2013 May 31;288(22):15843-53

Date

04/24/2013

Pubmed ID

23609438

Pubmed Central ID

PMC3668741

DOI

10.1074/jbc.M112.427187

Scopus ID

2-s2.0-84878408383 (requires institutional sign-in at Scopus site)   76 Citations

Abstract

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 antiproliferative 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 abolishing the expression and activity of KCa3.1 and PDGF β-receptors and inhibiting the rise in [Ca(2+)]i. The stimulation also attenuated the levels of phosphorylated CREB, c-Fos, and cyclin 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-shaped 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.

Author List

Bi D, Toyama K, Lemaître V, Takai J, Fan F, Jenkins DP, Wulff H, Gutterman DD, Park F, Miura H

MESH terms used to index this publication - Major topics in bold

Angiogenesis Inducing Agents
Atherosclerosis
Calcium Signaling
Calcium-Binding Proteins
Calmodulin-Binding Proteins
Cell Proliferation
Cells, Cultured
Cyclic AMP Response Element-Binding Protein
Humans
Intermediate-Conductance Calcium-Activated Potassium Channels
Membrane Transport Proteins
Microfilament Proteins
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Phosphorylation
Proto-Oncogene Proteins c-fos
Proto-Oncogene Proteins c-sis