Institution: | (1) Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Canada;(2) Department of Experimental Medicine and Surgery, McGill University, Montreal, Quebec, H3G 1Y6, Canada;(3) Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, Montreal, Quebec, H3G 1Y6, Canada;(4) Department of Biology, McGill University, Montreal, Quebec, H3G 1Y6, Canada;(5) Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3G 1Y6, Canada;(6) Departments of Human Genetics, Medicine and Biology, McGill University, Montreal, Quebec, H3G 1Y6, Canada;(7) Department of Medicine, McGill University, Montreal, Quebec, H3G 1Y6, Canada |
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 ( -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. |