Inhibition of MAPK stimulates the Ca2+ -dependent big-conductance K channels in cortical collecting duct.
The kidney plays a key role in maintaining potassium (K) homeostasis. K excretion is determined by the balance between K secretion and absorption in distal tubule segments such as the connecting tubule and cortical collecting duct. K secretion takes place by K entering principal cells (PC) from blood side through Na+, K+ -ATPase and being secreted into the lumen via both ROMK-like small-conductance K (SK) channels and Ca2+ -activated big-conductance K (BK) channels. K reabsorption occurs by stimulation of apical K/H-ATPase and inhibition of K recycling across the apical membrane in intercalated cells (IC). The role of ROMK channels in K secretion is well documented. However, the importance of BK channels in mediating K secretion is incompletely understood. It has been shown that their activity increases with high tubule flow rate and augmented K intake. However, BK channels have a low open probability and are mainly located in IC, which lack appropriate transporters for effective K secretion. Here we demonstrate that inhibition of ERK and P38 MAPKs stimulates BK channels in both PC and IC in the cortical collecting duct and that changes in K intake modulate their activity. Under control conditions, BK channel activity in PC was low but increased significantly by inhibition of both ERK and P38. Blocking MAPKs also increased channel open probability of BK in IC and thereby it may affect K backflux and net K absorption Thus, modulation of ERK and P38 MAPK activity is involved in controlling net K secretion in the distal nephron.
Li
Dimin
D
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Wang
Zhijian
Z
Sun
Peng
P
Jin
Yan
Y
Lin
Dao-Hong
DH
Hebert
Steven C
SC
Giebisch
Gerhard
G
Wang
Wen-Hui
WH
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D055592:Biophysical Phenomena; D001703:Biophysics; D015153:Blotting, Western; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008297:Male; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017828:Rifabutin / Q000031:analogs & derivatives; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D016227:Benzoquinones; D005419:Flavonoids; D047029:Lactams, Macrocyclic; D051036:Large-Conductance Calcium-Activated Potassium Channels; D017828:Rifabutin; C020754:herbimycin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D011188:Potassium; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one