title: Delayed rectifier K currents in NF1 Schwann cells. Pharmacological block inhibits proliferation.
abstract: K+(K) currents are related to the proliferation of many cell types and have a relationship to second messenger pathways implicated in regulation of the cell cycle in development and certain disease states. We examined the role of K currents in Schwann cells (SC) cultured from tumors that arise in the human disease neurofibromatosis type 1 (NF1). Comparisons were made between whole cell voltage clamp recordings from normal human SC cultures and from neurofibroma cultures and malignant peripheral nerve sheath tumor (MPNST) cell lines. The outward K currents of normal and tumor cells could be divided into three types based on pharmacology and macroscopic inactivation: (1) "A type" current blocked by 4-aminopyridine, (2) delayed rectifier (DR) current blocked by tetraethylammonium, and (3) biphasic current consisting of a combination of these two current types. The DR K current was present in MPNST- and neurofibroma-derived SC, but not in quiescent, nondividing, normal SC. DR currents were largest in MPNST-derived SC (50 pA/pF vs. 2.1-4.9 pA/pF in dividing and quiescent normal SC). Normal SC cultures had significantly more cells with A type current than cultures of MPNST and the plexiform neurofibroma. Conversely, MPNST and plexiform neurofibroma cultures had significantly more SC with DR current than did normal cultures, and these DR currents were significantly larger. In addition, the plexiform neurofibroma culture had significantly more cells with DR current than the dermal neurofibroma culture. K currents in SC from normal NF1 SC cultures had current abundances similar to GGF-exposed normal SC and the plexiform neurofibroma. We have established a link between DR K current blockade via TEA analogs and inhibition of proliferation of NF1 SC in vitro. In addition, a farnysyl transferase inhibitor (FTI), a blocker of Ras activation, blocked cell proliferation without blocking K currents in all cultures except a plexiform neurofibroma, suggesting that regulation of proliferation in neoplastic and normal SC in vitro is complex.
authors.affiliation: Division of Marine Biology and Fisheries, University of Miami Rosenstiel School, 4600 Rickenbacker Cswy, Miami, FL 33149, USA. lfieber@rsmas.miami.edu
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Fieber
authors.forename: Diana M
authors.initials: DM
authors.lastname: González
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wallace
authors.forename: David
authors.initials: D
authors.lastname: Muir
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D018929:Cell Culture Techniques; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D018317:Nerve Sheath Neoplasms / Q000378:metabolism*; D009456:Neurofibromatosis 1 / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism*; D019789:Tetraethylammonium / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019789:Tetraethylammonium; D015761:4-Aminopyridine