title: Intermediate-conductance calcium-activated potassium channel KCa3.1 and chloride channel modulate chemokine ligand (CCL19/CCL21)-induced migration of dendritic cells.
abstract: The role of ion channels is largely unknown in chemokine-induced migration in nonexcitable cells such as dendritic cells (DCs). Here, we examined the role of intermediate-conductance calcium-activated potassium channel (KCa3.1) and chloride channel (CLC3) in lymphatic chemokine-induced migration of DCs. The amplitude and kinetics of chemokine ligand (CCL19/CCL21)-induced Ca(2+) influx were associated with chemokine receptor 7 expression levels, extracellular-free Ca(2+) and Cl(-), and independent of extracellular K(+). Chemokines (CCL19 and CCL21) and KCa3.1 activator (1-ethyl-1,3-dihydro-2H-benzimidazol-2-one) induced plasma membrane hyperpolarization and K(+) efflux, which was blocked by 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole, suggesting that KCa3.1 carried larger conductance than the inward calcium release-activated calcium channel. Blockade of KCa3.1, low Cl(-) in the medium, and low dose of 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) impaired CCL19/CCL21-induced Ca(2+) influx, cell volume change, and DC migration. High doses of DIDS completely blocked DC migration possibly by significantly disrupting mitochondrial membrane potential. In conclusion, KCa3.1 and CLC3 are critical in human DC migration by synergistically regulating membrane potential, chemokine-induced Ca(2+) influx, and cell volume.
authors.affiliation: Center for Clinical and Translational Science, Creighton University of School of Medicine, Omaha, Neb.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Center for Clinical and Translational Science, Creighton University of School of Medicine, Omaha, Neb.
authors.forename: Rohit
authors.initials: R
authors.lastname: Gaurav
authors.affiliation: Center for Clinical and Translational Science, Creighton University of School of Medicine, Omaha, Neb. Electronic address: dkagr@creighton.edu.
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D020013:Calcium Signaling; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D054415:Chemokine CCL19 / Q000378:metabolism; D054421:Chemokine CCL21 / Q000378:metabolism; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D054400:Receptors, CCR7 / Q000378:metabolism; D057170:Translational Research, Biomedical
chemical_list: D001562:Benzimidazoles; C515460:CCL19 protein, human; C515478:CCL21 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D018118:Chloride Channels; C115376:ClC-3 channel; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D011720:Pyrazoles; D054400:Receptors, CCR7; C411671:TRAM 34; C102635:1-ethyl-2-benzimidazolinone; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid