Insulin-independent, MAPK-dependent stimulation of NKCC activity in skeletal muscle

Na+-K+-Cl- cotransporter (NKCC) activity in quiescent skeletal muscle is mo dest. However, ex vivo stimulation of muscle for as little as 18 contractio ns (1 min, 0.3 Hz) dramatically increased the activity of the cotransporter , measured as the bumetanide-sensitive Rb-86 influx, in both soleus and pla ntaris muscles. This activation of cotransporter activity remained relative ly constant for up to 10-Hz stimulation for 1 min, falling off at higher fr equencies (30-Hz stimulation for 1 min). Similarly, stimulation of skeletal muscle with adrenergic receptor agonists phenylephrine, isoproterenol, or epinephrine produced a dramatic stimulation of NKCC activity. It did not ap pear that stimulation of NKCC activity was a reflection of increased Na+-K-ATPase activity because insulin treatment did not stimulate NKCC activity, despite insulin's well-known stimulation of Na+-K+-ATPase activity. Stimul ation of NKCC activity could be blocked by pretreatment with inhibitors of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) activity, indic ating that activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2) MAPKs may be required. These data indicate a regulated NKCC activity i n skeletal muscle that may provide a significant pathway for potassium tran sport into skeletal muscle fibers.