title: The intermediate conductance calcium-activated potassium channel KCa3.1 regulates vascular smooth muscle cell proliferation via controlling calcium-dependent signaling.
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.
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Bi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Toyama
authors.forename: Vincent
authors.initials: V
authors.lastname: Lemaître
authors.forename: Jun
authors.initials: J
authors.lastname: Takai
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: David P
authors.initials: DP
authors.lastname: Jenkins
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
authors.forename: Frank
authors.initials: F
authors.lastname: Park
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miura
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000077214:Becaplermin; D020013:Calcium Signaling / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D000096985:Calponins
chemical_list: D043925:Angiogenesis Inducing Agents; D000077214:Becaplermin; D002135:Calcium-Binding Proteins; D002148:Calmodulin-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026901:Membrane Transport Proteins; D008840:Microfilament Proteins; D016760:Proto-Oncogene Proteins c-fos; D020574:Proto-Oncogene Proteins c-sis; D000096985:Calponins; C115163:CREB1 protein, human; C496923:KCNN4 protein, human; C479458:OSCP1 protein, human
keywords: Atherosclerosis; Calcium; Calcium Signaling; Cell Proliferation; Potassium Channels; Vascular Biology; Vascular Smooth Muscle Cells