Stromal cell-derived factor-1alpha directly modulates voltage-dependent currents of the action potential in mammalian neuronal cells.
Stromal cell-derived factor-1alpha (SDF-1alpha) is a chemokine whose receptor, CXCR4, is distributed in specific brain areas including hypothalamus. SDF-1alpha has recently been found to play important roles in neurons, although direct modulation of voltage-gated ionic channels has never been shown. In order to clarify this issue, we performed patch-clamp experiments in fetal mouse hypothalamic neurons in culture. SDF-1alpha (10 nm) decreased the peak and rising slope of the action potentials and spike discharge frequency in 22% of hypothalamic neurons tested. This effect was blocked by the CXCR4 antagonist AMD 3100 (1 microm) but not by the metabotropic glutamate receptor antagonist MCPG (500 microm), indicating a direct action of SDF-1alpha on its cognate receptor. This effect involved a depression of both inward and outward voltage-dependent currents of the action potential. We confirmed these effects in the human neuroblastoma cell line SH-SY5Y, which endogenously expresses CXCR4. Voltage-clamp experiments revealed that SDF-1alpha induced a 20% decrease in the peak of the tetrodotoxin-sensitive sodium current and tetraethylammonium-sensitive delayed rectifier potassium current, respectively. Both effects were concentration dependent, and blocked by AMD 3100 (200 nm). This dual effect was reduced or blocked by 0.4 mm GTPgammaS G-protein pre-activation or by pre-treatment with the G-protein inhibitor pertussis toxin (200 ng/mL), suggesting that it is mediated via activation of a G(i/o) protein. This study extends the functions of SDF-1alpha to a direct modulation of voltage-dependent membrane currents of neuronal cells.
Guyon
A
A
Institut de Pharmacologie Moléculaire et Cellulaire (IPMC)- UMR 6097 CNRS, Valbonne, France.
Rovère
C
C
Cervantes
A
A
Allaeys
I
I
Nahon
J L
JL
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001596:Benzylamines; D019256:Cadmium Chloride / Q000494:pharmacology; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D000080027:Cyclams; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007031:Hypothalamus / Q000166:cytology; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D018272:Porins / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D050994:Voltage-Dependent Anion Channels
D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D018272:Porins; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D026941:Sodium Channel Blockers; D050994:Voltage-Dependent Anion Channels; C474696:methyl-(4-carboxyphenyl)glycine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013779:Tetrodotoxin; D019789:Tetraethylammonium; D019256:Cadmium Chloride; C088327:plerixafor; D005998:Glycine