Haughey NJ, Holden CP, Nath A, Geiger JD.
J Neurovirol. 1998 Jun 3-6; 4: 353.
Department of Pharmacology, University of Manitoba, Winnipeg, Canada.
The HIV-1 trans-activating protein Tat has been previously shown to cause neuronal excitation and cell death. Because numerous cellular functions including survival are affected by changes in levels of intracellular calcium ([Ca2+]i), we determined the mechanism and source of Tat-induced increases in [Ca2+]i. Tat increased [Ca2+]i in a dose-dependant manner in both neurons and astrocytes. Initial calcium responses in neurons were smaller compared to astrocytes, but only neurons exhibited secondary increases in [Ca2+]i that were sustained and progressive. NMDA, non-NMDA and metabotropic excitatory amino acid receptor blockade as well as removal of extracellular calcium were without effect on Tat-induced increases in [Ca2+]i. Tat-induced increases in [Ca2+]i were significantly attenuated following pre-treatment with bradykinin (stimulates calcium release from IP3 sensitive stores) and by the IP3 antagonist TMB-8, but were unaffected by ryanodine. Pre-treatment with pertussis toxin, an inhibitor of receptor-Gi protein coupling or the phopholipase C inhibitor neomycin significantly reduced Tat-induced increases of [Ca2+]i and neomycin also inhibited Tat-induced neuronal cell death. These results suggest that Tat acts on neurons and astrocytes by a pertussis toxin sensitive mechanism to stimulate phopholipase C, increase levels of IP3 and release calcium from IP3-sensitive intracellular stores. Inhibiting this pathway at the level of phospholipase C is neuroprotective and thus suggests a link between Tat-induced [Ca2+]i dysregulation and neurotoxicity.
Publication Types:
Keywords:
- Astrocytes
- Bradykinin
- Calcium
- Calcium Channels
- Calcium Signaling
- Cell Death
- Gallic Acid
- Gene Products, tat
- Genes, tat
- HIV-1
- N-Methylaspartate
- Neurons
- Neurosciences
- Pertussis Toxin
- Ryanodine
- Ryanodine Receptor Calcium Release Channel
- TMB 8
- Type C Phospholipases
- genetics
Other ID:
UI: 102237417
From Meeting Abstracts