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Macrophage Migration Inhibitory Factor Increases Neuronal Delayed Rectifier K⁺ Current

¹Department of Physiology and Functional Genomics and McKnight Brain Institute and ²Department of Anesthesiology, University of Florida, Gainesville, Florida; ³Yale University School of Medicine, New Haven, Connecticut; and ⁴Department of Biochemistry and Molecular Cell Biology, University Hospital of the Rheinische-Westfälische Technische Hochschule Aachen University, Aachen, Germany

Submitted 12 May 2005; accepted in final form 26 October 2005

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 µM), 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.

This article has been cited by other articles:

				H. Li, Y. Gao, Y. Qi, M. J. Katovich, N. Jiang, L. N. Braseth, D. A. Scheuer, P. Shi, and C. Sumners Macrophage migration inhibitory factor in hypothalamic paraventricular nucleus neurons decreases blood pressure in spontaneously hypertensive rats FASEB J, September 1, 2008; 22(9): 3175 - 3185. [Abstract] [Full Text] [PDF]

				T. Matsuura, R. A. Harrison, A. D. Westwell, H. Nakamura, A. E. Martynyuk, and C. Sumners Basal and angiotensin II-inhibited neuronal delayed-rectifier K+ current are regulated by thioredoxin Am J Physiol Cell Physiol, July 1, 2007; 293(1): C211 - C217. [Abstract] [Full Text] [PDF]