Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity

Olimpia Meucci, Alessandro Fatatis, Arthur A. Simen, Trevor J. Bushell, Patrick W. Gray, Richard J. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

602 Scopus citations

Abstract

The HIV-1 envelope protein gp120 induces apoptosis in hippocampal neurons. Because chemokine receptors act as cellular receptors for HIV-1, we examined rat hippocampal neurons for the presence of functional chemokine receptors. Fura-2-based Ca imaging showed that numerous chemokines, including SDF-1α, RANTES, and fractalkine, affect neuronal Ca signaling, suggesting that hippocampal neurons possess a wide variety of chemokine receptors. Chemokines also blocked the frequency of spontaneous glutamatergic excitatory postsynaptic currents recorded from these neurons and reduced voltage- dependent Ca currents in the same neurons. Reverse transcription-PCR demonstrated the expression of CCR1, CCR4, CCR5, CCR9/10, CXCR2, CXCR4, and CX3CR1, as well as the chemokine fractalkine in these neurons. Both fractalkine and macrophage-derived chemokine (MDC) produced a time-dependent activation of extracellular response kinases (ERK)-1/2, whereas no activation of c-JUN NH2-terminal protein kinase (JNK)/stress-activated protein kinase, or p38 was evident. Furthermore, these two chemokines, as well as SDF-1α, activated the Ca- and cAMP-dependent transcription factor CREB. Several chemokines were able also to block gp120-induced apoptosis of hippocampal neurons, both in the presence and absence of the glial feeder layer. These data suggest that chemokine receptors may directly mediate gp120 neurotoxicity.

Original languageEnglish (US)
Pages (from-to)14500-14505
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number24
DOIs
StatePublished - Nov 24 1998

ASJC Scopus subject areas

  • General

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