Macrophage migration inhibitory factor increases neuronal delayed rectifier K+ current.
Macrophage migration inhibitory factor (MIF) has widespread actions in the immune, endocrine, and nervous systems. Previously, we reported that increases in the intracellular levels of MIF depress the firing of hypothalamus/brain stem neurons in culture, including the chronotropic actions of angiotensin II. The objective of this study was to investigate the effects of MIF on delayed rectifier K+ current (I(Kv)), one of the component currents whose activity contributes to neuronal firing. Intracellular perfusion of MIF (80 nM) into Sprague-Dawley rat neuronal cultures caused a significant increase in I(Kv), as measured by patch-clamp recordings. This effect was apparent by 3 min, and was maximal after 20-30 min. I(Kv) current density (pA/pF) increased from 31.58 +/- 2.36 in controls to 41.88 +/- 3.76 in MIF-treated neurons (mean +/- SE; n = 9; P < 0.01). MIF that had been inactivated by boiling did not alter I(Kv), and MIF-neutralizing antibodies abolished the action of recombinant MIF (rMIF). The stimulatory effect of MIF on I(Kv) current density was mimicked by intracellular application of either P1S-MIF (80 nM) or the peptide MIF-(50-65) (0.8-8 microM), both of which harbor the thiol-protein oxidoreductase (TPOR) activity of the MIF molecule. Conversely, neither C60S-MIF (80 nM) nor the MIF homologue D-dopachrome tautomerase (80 nM), both of which lack TPOR activity, altered I(Kv). Finally, the increase in I(Kv) produced by rMIF was abolished by the superoxide scavenger Tiron (1 mM). These studies indicate that the neuronal action of MIF includes a stimulatory action on I(Kv) that may be mediated by a TPOR/superoxide-scavenging mechanism.
Matsuura
Tomokazu
T
Department of Physiology and Functional Genomics and McKnight Brain Institute, University of Florida, Gainesville, FL 32610-0274, USA.
Sun
Chengwen
C
Leng
Lin
L
Kapurniotu
Aphrodite
A
Bernhagen
Jürgen
J
Bucala
Richard
R
Martynyuk
Anatoly E
AE
Sumners
Colin
C
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D051668:Delayed Rectifier Potassium Channels; D008263:Macrophage Migration-Inhibitory Factors