Simultaneous activation of p38 MAPK and p42/44 MAPK by ATP stimulates the K+ current I-TREK in cardiomyocytes

Living cells exhibit multiple K+ channel proteins; among these is the recen tly reported atypical two-pore domain K+ channel protein TREK-1. Most K+ cu rrents are modulated by neurohormones and under various pathological condit ions. Here, in rat ventricular cardiomyocytes using the whole-cell patch-cl amp technique, we characterize for the first time a native TREK-1-like curr ent (I-TREK) that is activated by ATP, a purine agonist applied at a microm olar range. This current is sensitive to arachidonic acid, intracellular ac idosis, and various K+ current inhibitors. Reverse transcription-polymerase chain reaction reveals the presence of a TREK-1-Iike mRNA in rat cardiomyo cytes that shows 93% identity with mouse TREK-1. ATP effects are greatly at tenuated in the presence of arachidonic acid or HCO3--induced intracellular acidosis. Using a series of inhibitors, we further demonstrate that the AT P-induced stimulation of I-TREK implies the activation of cytosolic phospho lipase A(2) and the release of arachidonic acid. These events require the s imultaneous involvement of p38 MAPK and p42/44 MAPK, respectively, via a cA MP-dependent protein kinase and a tyrosine kinase pathway, whereas the two MAPKs conjugate to activate a mitogen- and stress-activated protein kinase (MSK-1). Our results thus demonstrate the occurrence of a TREK-1-like curre nt in cardiac cells whose activation by purine agonists implies a dual-MAPK cytosolic pathway.