CHEMOKINES REGULATE HIPPOCAMPAL NEURONAL SIGNALING AND GP120 NEUROTOXICITY

The HIV-1 envelope protein gp120 induces apoptosis in hippocampal neur ons. Because chemokine receptors act as cellular receptors for HIV-1, we examined rat hippocampal neurons for the presence of functional che mokine receptors. Fura-2-based Ca imaging showed that numerous chemoki nes, including SDF-1 alpha, RANTES, and fractalkine, affect neuronal C a signaling, suggesting that hippocampal neurons possess a wide variet y of chemokine receptors. Chemokines also blocked the frequency of spo ntaneous glutamatergic excitatory postsynaptic currents recorded from these neurons and reduced voltage-dependent Ca currents in the same ne urons. Reverse transcription-PCR demonstrated the expression of CCR1, CCR4, CCR5, CCR9/10, CXCR2, CXCR4, and CX(3)CR1, as well as the chemok ine fractalkine in these neurons. Both fractalkine and macrophage-deri ved chemokine (MDC) produced a time dependent activation of extracellu lar response kinases (ERK)-1/2, whereas no activation of c-JUN NH2-ter minal protein kinase (JNK)/stress-activated protein kinase, or p38 was evident. Furthermore, these two chemokines, as well as SDF-1 alpha; a ctivated the Ca-and cAMP-dependent transcription factor CREB. Several chemokines were able also to block gp120-induced apoptosis of hippocam pal neurons, both in the presence and absence of the glial feeder laye r. These data suggest that chemokine receptors may directly mediate gp 120 neurotoxicity.