Regulation of the cardiac delayed rectifier K^+ channel by membrane PIP_2 and its physiological significance

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We have presented experimental evidence supporting the view that the slowly activating component of delayed rectifier K^+ current (I_<Ks>) is tonically inhibited by membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP_2) in guinea-pig cardiac myocytes (Ding, Toyoda & Matsuura, J.Biol.Chem.279,50726-50734,2004). The present research project further elucidated the physiological significance of the PIP_2 regulation of I_<Ks> in guinea-pig atrial myocytes using the whole-cell patch-clamp method. Enhancement of I_<Ks> by extracellular application of ATP (50 μM) or phenylephrine (50 μM) or by exposure to 〜70% hyposmotic extracellular solution was significantly attenuated by intracellular application of PIP_2(50 μM) or anti-PIP_2 monoclonal antibody (1:40 dilution) via a patch-electrode. These results indicate that the PIP_2 regulation is involved at least partly in the potentiation of I_<Ks> evoked by stimulation of some Gq-PLC coupled receptors (e.g., P2Y-and α_1-receptors) or by hyposmotic cell swelling. Bath application of ATP (50 μM) evoked a biphasic shortening of the action potential duration(APD), namely, a marked shortening observed within 〜1 min of ATP application (an initial phase) and a more moderate shortening which remained thereafter (late phase). Our results support that APD shortening in the late phase can be primarily ascribed to the potentiation of I_<Ks> by ATP, while the transient activation of I_<K,ACh> mainly contributes to APD shortening in the initial phase. Thus, the inhibitory action of PIP_2 on I_<Ks> may play an important physiological role in the regulation of membrane excitability in guinea-pig atrial myocytes.