Increased T-type Ca2+ channel activity as a determinant of cellular toxicity in neuronal cell lines expressing polyglutamine-expanded human androgen receptors.
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.
Sculptoreanu
A
A
Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, Canada.
Abramovici
H
H
Abdullah
A A
AA
Bibikova
A
A
Panet-Raymond
V
V
Frankel
D
D
Schipper
H M
HM
Pinsky
L
L
Trifiro
M A
MA
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
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine