title: Distinct modifications in Kv2.1 channel via chemokine receptor CXCR4 regulate neuronal survival-death dynamics.
abstract: The chemokine stromal cell-derived factor-1α (SDF-1α) has multiple effects on neuronal activity, survival, and death under conditions that generate a proinflammatory microenvironment within the brain, via signaling through C-X-C-type chemokine receptor 4 (CXCR4), although the underlying cellular/molecular mechanisms are unclear. Using rat hippocampal neurons, we investigated distinct modifications in the voltage-gated K⁺ (Kv) channel Kv2.1 in response to short- and long-term SDF-1α/CXCR4-mediated signaling as an underlying mechanism for CXCR4-dependent regulation of neuronal survival and death. Acute exposure of neurons to SDF-1α led to dynamic dephosphorylation and altered localization of Kv2.1 channel, resulting in enhanced voltage-dependent activation of Kv2.1-based delayed-rectifier Kv currents (I(DR)). These changes were dependent on CXCR4- and/or NMDA receptor-mediated activation of calcineurin and provide neuroprotection. However, prolonged SDF-1α treatment leads to CXCR4-mediated activation of p38 mitogen-activated protein kinase, resulting in phosphorylation of Kv2.1 at S800 and enhanced surface trafficking of the channel protein, resulting in increased I(DR)/Kv2.1 current density. This, in combination with sustained dephosphorylation-induced enhancement of the voltage-dependent activation of I(DR)/Kv2.1, predisposed neurons to excessive K⁺ efflux, a vital step for the neuronal apoptotic program. Such apoptotic death was dependent on CXCR4 and Kv2.1 function and was absent in cells expressing the Kv2.1-S800A mutant channel. Furthermore, similar modifications in Kv2.1 and CXCR4/Kv2.1-dependent apoptosis were observed following treatment of neurons with the human immunodeficiency virus-1 (HIV-1) glycoprotein gp120. Therefore, distinct modifications in Kv2.1 in response to short- and long-term CXCR4-mediated signaling could provide a basis for neuroprotection or apoptosis in neuropathologies, such as neuroinflammation, stroke, brain tumors, and HIV-associated neurodegeneration.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Shepherd
authors.forename: Lipin
authors.initials: L
authors.lastname: Loo
authors.forename: Raeesa P
authors.initials: RP
authors.lastname: Gupte
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Mickle
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D054377:Chemokine CXCL12 / Q000494:pharmacology / Q000502:physiology*; D004347:Drug Interactions; D005260:Female; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D050505:Mutant Proteins / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000819:agonists / Q000502:physiology*; D051669:Shab Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D015699:HIV Envelope Protein gp120; C496991:Kcnb1 protein, rat; D050505:Mutant Proteins; D019718:Receptors, CXCR4; D051669:Shab Potassium Channels; C514793:gp120 protein, Human immunodeficiency virus 1; D048051:p38 Mitogen-Activated Protein Kinases; D019703:Calcineurin; D016559:Tacrolimus