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 cel l lines that expressed normal or glutamine-expanded human androgen receptor s (polyGln-expanded AR) either transiently or stably. The cell lines expres s a unique, low-threshold, transient type of Ca-2+ current that is not affe cted by L-type Ca-2+ channel blocker (PN 200-110), N-type Ca2+ channel bloc ker (omega-conotoxin GVIA) or P-type Ca2+ channel blocker (Agatoxin IVA) bu t is blocked by either Cd2+ or Ni2+. This pharmacological profile most clos ely 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 sig nificantly changed the steady-state activation in cells transfected with ex panded AR. The observed negative shift in steady-state activation results i n a large increase in the T-type Ca2+ channel window current. We suggest th at Ca2+ overload due to abnormal voltage-dependence of transient Ca2+ chann el activation may contribute to motor neuron toxicity in spinobulbar muscul ar atrophy (SBMA). This hypothesis is supported by the additional finding t hat, at concentrations that selectively block T-type Ca2+ channel currents, Ni2+ significantly reduced cell death in cell lines transfected with polyG ln-expanded AR.