Macrophage migration inhibitory factor: an intracellular inhibitor of angiotensin II-induced increases in neuronal activity.
Angiotensin II (Ang II) elicits Ang II type 1 receptor (AT1-R)-mediated increases in neuronal firing within the hypothalamus and brainstem that are ultimately responsible for physiological actions such as increased blood pressure and fluid intake. Although there is a growing literature on the intracellular mechanisms that mediate the actions of Ang II via AT1-R in neurons, little is known about the mechanisms that diminish or "switch-off" the neuronal chronotropic action of Ang II. In the present study, we identified macrophage migration inhibitory factor (MIF) as an intracellular inhibitor of the actions of Ang II in neurons. The evidence is as follows. First, Ang II, acting via AT1-R, increases the intracellular levels of MIF in neurons cultured from rat hypothalamus and brainstem. Second, elevation of intracellular MIF by Ang II prevents further chronotropic actions of this peptide. Third, intracellular application of exogenous recombinant MIF abolishes the Ang II-induced chronotropic action in neurons. Finally, intracellular application of the MIF peptide fragment MIF-(50-65), which harbors the thiol oxidoreductase property of the MIF molecule, mimics the inhibitory actions of MIF on Ang II-stimulated neuronal firing. Thus, this study is the first to demonstrate the existence of an intracellular negative regulator of Ang II-induced actions in neurons and indicates that MIF may act as a physiological brake for the chronotropic effects of Ang II in rat neurons.
Sun
Chengwen
C
Department of Physiology and Functional Genomics and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0274, USA.
Li
Hongwei
H
Leng
Lin
L
Raizada
Mohan K
MK
Bucala
Richard
R
Sumners
Colin
C
D000200:Action Potentials / Q000502:physiology; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000502:physiology*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010088:Oxidoreductases / Q000378:metabolism; D010446:Peptide Fragments; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D008263:Macrophage Migration-Inhibitory Factors; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D010088:Oxidoreductases