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The Journal of Neuroscience, November 19, 2008, 28(47):12231-12240; doi:10.1523/JNEUROSCI.3212-08.2008

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Cellular/Molecular
RANTES Modulates the Release of Glutamate in Human Neocortex

Veronica Musante,¹ Fabio Longordo,³ Elisa Neri,¹ Marco Pedrazzi,² Fotios Kalfas,⁴ Paolo Severi,⁴ Maurizio Raiteri,^1,5 and Anna Pittaluga^1,5

¹Section of Pharmacology and Toxicology and ²Section of Biochemistry, Department of Experimental Medicine, University of Genoa, 16148 Genoa, Italy, ³Biozentrum, University of Basel, CH 4056 Basel, Switzerland, ⁴Division of Neurosurgery, Galliera Hospital, 16128 Genoa, Italy, and ⁵Center of Excellence for Biomedical Research, University of Genoa, 16132 Genoa, Italy

Correspondence should be addressed to Anna Pittaluga, Department of Experimental Medicine, Section of Pharmacology and Toxicology, Viale Cembrano, 16148 Genoa, Italy. Email: pittalug{at}pharmatox.unige.it

The effects of the recombinant chemokine human RANTES (hRANTES) on the release of glutamate from human neocortex glutamatergic nerve endings were investigated. hRANTES facilitated the spontaneous release of d [³H]D-aspartate ([³H]DASP-) by binding Pertussis toxin-sensitive G-protein-coupled receptors (GPCRs), whose activation caused Ca²⁺ mobilization from inositol trisphosphate-sensitive stores and cytosolic tyrosine kinase-mediated phosphorylations. Facilitation of release switched to inhibition when the effects of hRANTES on the 12 mM K⁺-evoked [³H]D-ASP exocytosis were studied. Inhibition of exocytosis relied on activation of Pertussis toxin-sensitive GPCRs negatively coupled to adenylyl cyclase. Both hRANTES effects were prevented by met-RANTES, an antagonist at the chemokine receptors (CCRs) of the CCR1, CCR3, and CCR5 subtypes. Interestingly, human neocortex glutamatergic nerve endings seem to possess all three receptor subtypes. Blockade of CCR1 and CCR5 by antibodies against the extracellular domain of CCRs prevented both the hRANTES effect on [³H]D-ASP release, whereas blockade of CCR3 prevented inhibition, but not facilitation, of release. The effects of RANTES on the spontaneous and the evoked release of [³H]D-ASP were also observed in experiments with mouse cortical synaptosomes, which may therefore represent an appropriate animal model to study RANTES-induced effects on neurotransmission. It is concluded that glutamate transmission can be modulated in opposite directions by RANTES acting at distinct CCR receptor subtypes coupled to different transduction pathways, consistent with the multiple and sometimes contrasting effects of the chemokine.

Key words: human RANTES; human neocortex; basal glutamate release; evoked glutamate release; chemokine receptors; cytokine

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Received July 10, 2008; revised Sept. 22, 2008; accepted Sept. 24, 2008.

Correspondence should be addressed to Anna Pittaluga, Department of Experimental Medicine, Section of Pharmacology and Toxicology, Viale Cembrano, 16148 Genoa, Italy. Email: pittalug{at}pharmatox.unige.it

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