HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism

Kelly A. Krogh, Elizabeth Lyddon, Stanley A. Thayer

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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 Ca2+ 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 Ca2+. 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 Ca2+ influx and could reveal targets for the treatment of HIV-associated neurocognitive disorders.

Original languageEnglish (US)
Pages (from-to)354-366
Number of pages13
JournalJournal of Neurochemistry
Volume132
Issue number3
DOIs
StatePublished - Feb 2015

Bibliographical note

Publisher Copyright:
© 2014 International Society for Neurochemistry.

Keywords

  • Actin
  • HIV Tat
  • NMDA receptor
  • ROCK
  • intracellular calcium
  • neurotoxicity

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