title: HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism.
abstract: HIV-associated neurocognitive disorders afflict approximately half of HIV-infected patients. HIV-infected cells within the CNS release neurotoxic viral proteins such as the transactivator of transcription (Tat). Tat caused a biphasic change in NMDAR function; NMDA-evoked increases in intracellular Ca(2+) were initially potentiated following 16 h exposure to Tat and then adapted by gradually returning to baseline by 24 h. Following Tat-induced NMDAR potentiation, a RhoA/Rho-associated protein kinase (ROCK) signaling pathway was activated; a subsequent remodeling of the actin cytoskeleton reduced NMDA-evoked increases in intracellular Ca(2+) . Pharmacologic or genetic inhibition of RhoA or ROCK failed to affect potentiation, but prevented adaptation of NMDAR function. Activation of RhoA/ROCK signaling increases the formation of filamentous actin. Drugs that prevent changes to filamentous actin blocked adaptation of NMDAR function following Tat-induced potentiation, whereas stimulating either depolymerization or polymerization of actin attenuated NMDAR function. These findings indicate that Tat activates a RhoA/ROCK signaling pathway resulting in actin remodeling and subsequent reduction of NMDAR function. Adaptation of NMDAR function may be a mechanism to protect neurons from excessive Ca(2+) influx and could reveal targets for the treatment of HIV-associated neurocognitive disorders.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Krogh
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lyddon
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Thayer
mesh_terms: D000199:Actins / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D061251:Primary Cell Culture; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D000199:Actins; D018690:Excitatory Amino Acid Agonists; D054322:tat Gene Products, Human Immunodeficiency Virus; D016202:N-Methylaspartate; D004247:DNA; D020742:rhoA GTP-Binding Protein; D002118:Calcium
keywords: Actin; HIV Tat; NMDA receptor; ROCK; intracellular calcium; neurotoxicity