TY - JOUR
T1 - The chemokine CXCL12 and the HIV-1 envelope protein gp120 regulate spontaneous activity of Cajal-Retzius cells in opposite directions
AU - Marchionni, Ivan
AU - Beaumont, Michael
AU - Maccaferri, Gianmaria
PY - 2012/7
Y1 - 2012/7
N2 - Activation of the CXC chemokine receptor 4 (CXCR4) in Cajal-Retzius cells by CXC chemokine ligand 12 (CXCL12) is important for controlling their excitability. CXCR4 is also a co-receptor for the glycoprotein 120 (gp120) of the envelope of the human immunodeficiency virus type 1 (HIV-1), and binding of gp120 to CXCR4 may produce pathological effects. In order to study CXCR4-dependent modulation of membrane excitability, we recorded in cell-attached configuration spontaneous action currents from hippocampal stratum lacunosum-moleculare Cajal-Retzius cells of the CXCR4-EGFP mouse. CXCL12 (50 nm) powerfully inhibited firing independently of synaptic transmission, suggesting that CXCR4 regulates an intrinsic conductance. This effect was prevented by conditioning slices with BAPTA-AM (200 μm), and by blockers of the BK calcium-dependent potassium channels (TEA (1 mm), paxilline (10 μm) and iberiotoxin (100 nm)). In contrast, exposure to gp120 (pico- to nanomolar range, alone or in combination with soluble cluster of differentiation 4 (CD4)), enhanced spontaneous firing frequency. This effect was prevented by the CXCR4 antagonist AMD3100 (1 μm) and was absent in EGFP-negative stratum lacunosum-moleculare interneurons. Increased excitability was prevented by treating slices with BAPTA-AM or bumetanide, suggesting that gp120 activates a mechanism that is both calcium- and chloride-dependent. In conclusion, our results demonstrate that CXCL12 and gp120 modulate the excitability of Cajal-Retzius cells in opposite directions. We propose that CXCL12 and gp120 either generate calcium responses of different strength or activate distinct pools of intracellular calcium, leading to agonist-specific responses, mediated by BK channels in the case of CXCL12, and by a chloride-dependent mechanism in the case of gp120.
AB - Activation of the CXC chemokine receptor 4 (CXCR4) in Cajal-Retzius cells by CXC chemokine ligand 12 (CXCL12) is important for controlling their excitability. CXCR4 is also a co-receptor for the glycoprotein 120 (gp120) of the envelope of the human immunodeficiency virus type 1 (HIV-1), and binding of gp120 to CXCR4 may produce pathological effects. In order to study CXCR4-dependent modulation of membrane excitability, we recorded in cell-attached configuration spontaneous action currents from hippocampal stratum lacunosum-moleculare Cajal-Retzius cells of the CXCR4-EGFP mouse. CXCL12 (50 nm) powerfully inhibited firing independently of synaptic transmission, suggesting that CXCR4 regulates an intrinsic conductance. This effect was prevented by conditioning slices with BAPTA-AM (200 μm), and by blockers of the BK calcium-dependent potassium channels (TEA (1 mm), paxilline (10 μm) and iberiotoxin (100 nm)). In contrast, exposure to gp120 (pico- to nanomolar range, alone or in combination with soluble cluster of differentiation 4 (CD4)), enhanced spontaneous firing frequency. This effect was prevented by the CXCR4 antagonist AMD3100 (1 μm) and was absent in EGFP-negative stratum lacunosum-moleculare interneurons. Increased excitability was prevented by treating slices with BAPTA-AM or bumetanide, suggesting that gp120 activates a mechanism that is both calcium- and chloride-dependent. In conclusion, our results demonstrate that CXCL12 and gp120 modulate the excitability of Cajal-Retzius cells in opposite directions. We propose that CXCL12 and gp120 either generate calcium responses of different strength or activate distinct pools of intracellular calcium, leading to agonist-specific responses, mediated by BK channels in the case of CXCL12, and by a chloride-dependent mechanism in the case of gp120.
UR - http://www.scopus.com/inward/record.url?scp=84863004164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863004164&partnerID=8YFLogxK
U2 - 10.1113/jphysiol.2011.224873
DO - 10.1113/jphysiol.2011.224873
M3 - Article
C2 - 22473778
AN - SCOPUS:84863004164
VL - 590
SP - 3185
EP - 3202
JO - Journal of Physiology
JF - Journal of Physiology
SN - 0022-3751
IS - 13
ER -