BACKGROUND: Voltage-gated potassium (K(v)) channels are among the earliest ion channels to appear during brain development, suggesting a functional requirement for progenitor cell proliferation and/or differentiation. We tested this hypothesis, using human neural progenitor cells (hNPCs) as a model system. METHODOLOGY/PRINCIPAL FINDINGS: In proliferating hNPCs a broad spectrum of K(v) channel subtypes was identified using quantitative real-time PCR with a predominant expression of the A-type channel K(v)4.2. In whole-cell patch-clamp recordings K(v) currents were separated into a large transient component characteristic for fast-inactivating A-type potassium channels (I(A)) and a small, sustained component produced by delayed-rectifying channels (I(K)). During differentiation the expression of I(A) as well as A-type channel transcripts dramatically decreased, while I(K) producing delayed-rectifiers were upregulated. Both K(v) currents were differentially inhibited by selective neurotoxins like phrixotoxin-1 and alpha-dendrotoxin as well as by antagonists like 4-aminopyridine, ammoniumchloride, tetraethylammonium chloride and quinidine. In viability and proliferation assays chronic inhibition of the A-type currents severely disturbed the cell cycle and precluded proper hNPC proliferation, while the blockade of delayed-rectifiers by alpha-dendrotoxin increased proliferation. CONCLUSIONS/SIGNIFICANCE: These findings suggest that A-type potassium currents are essential for proper proliferation of immature multipotent hNPCs.
BACKGROUND: Voltage-gated potassium (K(v)) channels are among the earliest ion channels to appear during brain development, suggesting a functional requirement for progenitor cell proliferation and/or differentiation. We tested this hypothesis, using human neural progenitor cells (hNPCs) as a model system. METHODOLOGY/PRINCIPAL FINDINGS: In proliferating hNPCs a broad spectrum of K(v) channel subtypes was identified using quantitative real-time PCR with a predominant expression of the A-type channel K(v)4.2. In whole-cell patch-clamp recordings K(v) currents were separated into a large transient component characteristic for fast-inactivating A-type potassium channels (I(A)) and a small, sustained component produced by delayed-rectifying channels (I(K)). During differentiation the expression of I(A) as well as A-type channel transcripts dramatically decreased, while I(K) producing delayed-rectifiers were upregulated. Both K(v) currents were differentially inhibited by selective neurotoxins like phrixotoxin-1 and alpha-dendrotoxin as well as by antagonists like 4-aminopyridine, ammoniumchloride, tetraethylammonium chloride and quinidine. In viability and proliferation assays chronic inhibition of the A-type currents severely disturbed the cell cycle and precluded proper hNPC proliferation, while the blockade of delayed-rectifiers by alpha-dendrotoxin increased proliferation. CONCLUSIONS/SIGNIFICANCE: These findings suggest that A-type potassium currents are essential for proper proliferation of immature multipotent hNPCs.
Authors: Christine Beeton; Michael W Pennington; Heike Wulff; Satendra Singh; Daniel Nugent; George Crossley; Ilya Khaytin; Peter A Calabresi; Chao-Yin Chen; George A Gutman; K George Chandy Journal: Mol Pharmacol Date: 2005-01-21 Impact factor: 4.436
Authors: Nadja Spitzer; Gregory S Sammons; Heather M Butts; Lawrence M Grover; Elmer M Price Journal: J Cell Physiol Date: 2011-12 Impact factor: 6.384
Authors: Mi-hyeon You; Min Seok Song; Seul Ki Lee; Pan Dong Ryu; So Yeong Lee; Dae-yong Kim Journal: Acta Pharmacol Sin Date: 2012-12-10 Impact factor: 6.150