Basal and angiotensin II-inhibited neuronal delayed-rectifier K+ current are regulated by thioredoxin.
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.
Matsuura
Tomokazu
T
Dept. of Physiology and Functional Genomics, College of Medicine, University of Florida, Box 100274, 1600 SW Archer Rd., Gainesville, FL 32610-0274, USA.
Harrison
Rachael A
RA
Westwell
Andrew D
AD
Nakamura
Hajime
H
Martynyuk
Anatoly E
AE
Sumners
Colin
C
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D052160:Benzothiazoles / Q000494:pharmacology; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011490:Protein Disulfide Reductase (Glutathione) / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
C515226:AW 464; D052160:Benzothiazoles; D003512:Cyclohexanones; D051668:Delayed Rectifier Potassium Channels; D012333:RNA, Messenger; D000804:Angiotensin II; D013879:Thioredoxins; D011490:Protein Disulfide Reductase (Glutathione)