Enhancement of delayed rectifier K+ current by P2‐purinoceptor stimulation in guinea‐pig atrial cells.

Abstract

1. We studied the effects of P2-purinoceptor stimulation on the delayed rectifier K+ current (IK) 3. External ADP also enhanced IK in a dose-dependent manner with a K% of 3-65 /UM, whereas adenosine (100 /,M) failed to evoke this response. Theophylline (500 ,tM), a blocker of the P1-purinoceptor, did not antagonize the stimulating action of ATP on IK. These results indicate that IK was enhanced via P2-purinoceptors. 4. External ATP or ADP did not produce a significant change in the current kinetics of IK.

Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

“…It has previously been demonstrated in guinea pig cardiac myocytes that the activation of P2Y receptor stimulates PLC and thereby depletes plasma membrane PtdIns(4,5)P 2 that is required for maintaining the activity of the ATP-sensitive K ϩ channels (20). We next checked whether the possible reduction of PtdIns(4,5)P 2 levels mediates potentiation of I Ks associated with P2Y receptor stimulation (18,19). As demonstrated in Fig.…”

“…5D) when evaluated by monitoring the changes in tail current amplitude elicited upon repolarization to Ϫ50 mV following 2-s depolarization to ϩ30 mV. In guinea pig atrial myocytes, increasing the concentration of ATP above 50 M caused no further increase in I Ks (18), showing that 50 M ATP evokes a maximal enhancement of I Ks .…”

“…It is assumed that the APD shortening by extracellular ATP is primarily mediated through its stimulatory action on two distinct K ϩ channels, namely, I Ks (18,19) and the muscarinic K ϩ channels (35)(36)(37)(38). Whereas potentiation of I Ks by extracellular ATP remains rather stable over a period of at least 5 min during exposure to the agonist, activation of I K,ACh by micromolar concentrations of ATP is characterized by its rapid decay to the pre-agonist (control) levels within 1-2 min despite the continued presence of the agonist (36 -38).…”

“…Hilgemann and Ball (12) revealed for the first time that the Na ϩ /Ca 2ϩ exchanger and ATP-sensitive K ϩ channels are positively regulated by endogenous PtdIns(4,5)P 2 in guinea pig cardiac cell membranes. Recent studies have demonstrated that PtdIns(4,5)P 2 modulates the function of a number of ion channels, including many inwardly rectifying K ϩ channels (13-15), the HERG K ϩ channel (16) and voltage-gated P/Q-type Ca 2ϩ channels (17).We have previously shown that, in guinea pig cardiac myocytes, the stimulation of P2Y receptor (G protein-coupled ATP receptor) by extracellular ATP markedly enhances I Ks through a mechanism that appears to be independent of either the activation of PKC or the elevation of intracellular Ca 2ϩ (18,19). Moreover, it was recently demonstrated in guinea pig ventricular myocytes that the stimulation of P2Y receptor evokes a pronounced reduction in the activity of ATP-sensitive K ϩ channels through a PLC-induced depletion of membrane PtdIns(4,5)P 2 (20).…”

“…We have previously shown that, in guinea pig cardiac myocytes, the stimulation of P2Y receptor (G protein-coupled ATP receptor) by extracellular ATP markedly enhances I Ks through a mechanism that appears to be independent of either the activation of PKC or the elevation of intracellular Ca 2ϩ (18,19). Moreover, it was recently demonstrated in guinea pig ventricular myocytes that the stimulation of P2Y receptor evokes a pronounced reduction in the activity of ATP-sensitive K ϩ channels through a PLC-induced depletion of membrane PtdIns(4,5)P 2 (20).…”