title: Increased T-type Ca2+ channel activity as a determinant of cellular toxicity in neuronal cell lines expressing polyglutamine-expanded human androgen receptors.
abstract: We have analyzed Ca2+ currents in two neuroblastoma-motor neuron hybrid cell lines that expressed normal or glutamine-expanded human androgen receptors (polyGln-expanded AR) either transiently or stably. The cell lines express a unique, low-threshold, transient type of Ca2+ current that is not affected by L-type Ca2+ channel blocker (PN 200-110), N-type Ca2+ channel blocker (omega-conotoxin GVIA) or P-type Ca2+ channel blocker (Agatoxin IVA) but is blocked by either Cd2+ or Ni2+. This pharmacological profile most closely resembles that of T-type Ca2+ channels [1-3]. Exposure to androgen had no effect on control cell lines or cells transfected with normal AR but significantly changed the steady-state activation in cells transfected with expanded AR. The observed negative shift in steady-state activation results in a large increase in the T-type Ca2+ channel window current. We suggest that Ca2+ overload due to abnormal voltage-dependence of transient Ca2+ channel activation may contribute to motor neuron toxicity in spinobulbar muscular atrophy (SBMA). This hypothesis is supported by the additional finding that, at concentrations that selectively block T-type Ca2+ channel currents, Ni2+ significantly reduced cell death in cell lines transfected with polyGln-expanded AR.
authors.affiliation: Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Sculptoreanu
authors.forename: H
authors.initials: H
authors.lastname: Abramovici
authors.forename: A A
authors.initials: AA
authors.lastname: Abdullah
authors.forename: A
authors.initials: A
authors.lastname: Bibikova
authors.forename: V
authors.initials: V
authors.lastname: Panet-Raymond
authors.forename: D
authors.initials: D
authors.lastname: Frankel
authors.forename: H M
authors.initials: HM
authors.lastname: Schipper
authors.forename: L
authors.initials: L
authors.lastname: Pinsky
authors.forename: M A
authors.initials: MA
authors.lastname: Trifiro
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D006801:Humans; D008564:Membrane Potentials; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine