Cross-talk between beta(1)-adrenoceptors and ET(A) receptors in modulation of the slow component of delayed rectifier K(+) currents.
Delayed rectifier K(+) currents (I(K)) play a critical role in determining cardiac action potential duration (APD). Modulation of I(K) affects cardiac excitability critically. There are three components of cardiac delayed rectifier, and the slowly activating component (I(Ks)) is influenced strongly by a variety of stimuli. Plasma levels of noradrenaline and endothelin are elevated in heart failure, and arrhythmias are promoted by such humoral abnormalities through modulation of ion channels. It has been reported that protein kinase A (PKA) and protein kinase C (PKC) modulate I(Ks) from human minK in a complex manner. In the present study, we coexpressed human minK with the human beta(1)-adrenoceptor (hbeta(1)AR) and the endothelin receptor subtype A (hET(A)R) in Xenopus oocytes and investigated the effects of receptor activation on the currents (I(Ks)) flowing through the oocytes. ET-1 modulated I(Ks) biphasically: a transient increase followed by a decrease. The PKC inhibitor chelerythrine completely inhibited the effects of ET-1. Intracellular EGTA abolished the transient increase by ET-1 and partially inhibited the subsequent decrease in the currents. When I(Ks) was increased by 10(-6) M isoproterenol (ISO), ET-1 did not increase but rather decreased the current to an even greater extent than under control conditions. In addition, the effects of ISO on I(Ks) were suppressed by ET(A)R stimulation. These data indicate that I(Ks) can be regulated by cross-talk between the ET(A)R and beta(1)AR systems in addition to direct regulation by each receptor system.
Lin
Changqing
C
Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Nagai
Mirei
M
Ishigaki
Daisuke
D
Hayasaka
Kiyoshi
K
Endoh
Masao
M
Ishii
Kuniaki
K
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D003001:Cloning, Molecular / Q000187:drug effects; D004558:Electric Stimulation; D004594:Electrophysiology; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D044022:Receptor, Endothelin A / Q000187:drug effects*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects*; D014981:Xenopus
D000318:Adrenergic beta-Agonists; D019332:Endothelin-1; D015221:Potassium Channels; D044022:Receptor, Endothelin A; D018342:Receptors, Adrenergic, beta-1; D007545:Isoproterenol