ATP-sensitive potassium channels mediate hyperosmotic stimulation of NKCC in slow-twitch muscle.
In mildly hyperosmotic medium, activation of the Na+ -K+ -2Cl- cotransporter (NKCC) counteracts skeletal muscle cell water loss, and compounds that stimulate protein kinase A (PKA) activity inhibit the activation of the NKCC. The aim of this study was to determine the mechanism for PKA inhibition of NKCC activity in resting skeletal muscle. Incubation of rat slow-twitch soleus and fast-twitch plantaris muscles in isosmotic medium with the PKA inhibitors H-89 and KT-5720 caused activation of the NKCC only in the soleus muscle. NKCC activation caused by PKA inhibition was insensitive to MEK MAPK inhibitors and to insulin but was abolished by the PKA stimulators isoproterenol and forskolin. Furthermore, pinacidil [an ATP-sensitive potassium (KATP) channel opener] or inhibition of glycolysis increased NKCC activity in the soleus muscle but not in the plantaris muscle. Preincubation of the soleus muscle with glibenclamide (a KATP channel inhibitor) prevented the NKCC activation by hyperosmolarity, PKA inhibition, pinacidil, and glycolysis inhibitors. In contrast, glibenclamide stimulated NKCC activity in the plantaris muscle. In cells stably transfected with the Kir6.2 subunit of the of KATP channel, inhibition of glycolysis activated potassium current and NKCC activity. We conclude that activation of KATP channels in slow-twitch muscle is necessary for activation of the NKCC and cell volume restoration in hyperosmotic conditions.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Aidar R
AR
Gosmanov
Zheng
Z
Fan
Xianqiang
X
Mi
Edward G
EG
Schneider
Donald B
DB
Thomason
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006982:Hypertonic Solutions / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012414:Rubidium Radioisotopes; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D013449:Sulfonamides; D014162:Transfection; D014867:Water / Q000378:metabolism; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D006982:Hypertonic Solutions; D007004:Hypoglycemic Agents; D007328:Insulin; D007546:Isoquinolines; D024661:Potassium Channels, Inwardly Rectifying; D012414:Rubidium Radioisotopes; D028021:Sodium-Potassium-Chloride Symporters; D013449:Sulfonamides; D014867:Water; D000255:Adenosine Triphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide