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NERVOUS SYSTEM CELL BIOLOGY

Basal and angiotensin II-inhibited neuronal delayed-rectifier K⁺ current are regulated by thioredoxin

¹Department of Physiology and Functional Genomics and McKnight Brain Institute, University of Florida, Gainesville, Florida; ²Department of Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom; ³Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Sakyo, Kyoto, Japan; and ⁴Department of Anesthesiology, University of Florida, Gainesville, Florida

Submitted 11 December 2006 ; accepted in final form 12 March 2007

In previous studies, we determined that macrophage migration inhibitory factor (MIF), acting intracellularly via its intrinsic thiol-protein oxidoreductase (TPOR) activity, stimulates basal neuronal delayed-rectifier K⁺ current (I_Kv) and inhibits basal and angiotensin (ANG) II-induced increases in neuronal activity. These findings are the basis for our hypothesis that MIF is a negative regulator of ANG II actions in neurons. MIF has recently been recategorized as a member of the thioredoxin (Trx) superfamily of small proteins. In the present study we have examined whether Trx influences basal and ANG II-modulated I_Kv in an effort to determine whether the Trx superfamily can exert a general regulatory influence over neuronal activity and the actions of ANG II. Intracellular application of Trx (0.8–80 nM) into rat hypothalamic/brain stem neurons in culture increased neuronal I_Kv, as measured by voltage-clamp recordings. This effect of Trx was abolished in the presence of the TPOR inhibitor PMX 464 (800 nM). Furthermore, the mutant protein recombinant human C32S/C35S-Trx, which lacks TPOR activity, failed to alter neuronal I_Kv. Trx applied at a concentration (0.08 nM) that does not alter basal I_Kv abolished the inhibition of neuronal I_Kv produced by ANG II (100 nM). Given our observation that ANG II increases Trx levels in neuronal cultures, it is possible that Trx (like MIF) has a negative regulatory role over basal and ANG II-stimulated neuronal activity via modulation of I_Kv. Moreover, these data suggest that TPOR may be a general mechanism for negatively regulating neuronal activity.

thiol-protein oxidoreductase; patch clamp; neuronal activity