β3-Adrenergic regulation of an ion channel in the heart—inhibition of the slow delayed rectifier potassium current IKs in guinea pig ventricular myocytes

Abstract

We have demonstrated a functional coupling between the beta(3)-adrenoceptor and ion channel function in the mammalian heart. Our findings point to a potential role for beta(3)-adrenoceptors in cardiac electrophysiology and pathophysiology.

Induction of β3-Adrenergic Receptor Functional Expression following Chronic Stimulation with Noradrenaline in Neonatal Rat Cardiomyocytes

“…Gauthier et al (1998) have also reported that NOR induced a negative inotropic effect when ␣-and ␤ 1 /␤ 2 -ARs were inhibited in human heart. Similarly, ␤ 3 -AR decreased potassium channel activity in the presence of ␤ 1 -and ␤ 2 -antagonists in guinea pig cardiomyocytes (Bosch et al, 2002). These observations indicate that ␤ 3 -ARs are not involved in the regulation of the cardiac function in normal physiological conditions (neonatal cardiomyocytes; this study) or that this subtype plays a minor role in the modulation of the functional response (human and guinea pig).…”

“…␤ 3 -AR-mediated decrease in cardiac contractility involves coupling to G i/o protein(s) and activation of constitutively expressed endothelial nitric-oxide synthase and the subsequent generation of NO (Gauthier et al, 1998;Kitamura et al, 2000;Varghese et al, 2000;Brixius et al, 2004). Furthermore, the functional activity of ionic currents such as L-type Ca 2ϩ and potassium I(Ks) are reduced by ␤ 3 -AR stimulation, which also modulates cardiac contractility (Kitamura et al, 2000;Cheng et al, 2001;Bosch et al, 2002;Morimoto et al, 2004). Interestingly, ␤ 3 -AR expression level increases in failing myocardium in human (Moniotte et al, 2001) and dog (Cheng et al, 2001), contributing to the depression of cardiac function (Morimoto et al, 2004).…”

Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on IKs downregulation and blunted β-adrenergic activation

“…β2-A signaling could modulate the function of these I Ks channels even in the absence of exogenous β-A agonists [31]. β3-A regulation of I Ks has also been reported, although with different results in different models: β3-AR stimulation enhanced I Ks in Xenopus oocytes expressing human KvLQT1/MinK channels [32], but inhibited the current in guinea-pig ventricular myocytes [33]. From the three receptor subtypes (β1, β2 and β3) examined in the present study, only β1 expression showed a clear and sustained decrease compatible with the decreased β-A responsiveness of I Ks in AVB cells.…”

β3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current

“…Because contractility of a trabeculum is a more integrated response than I Ca,L amplitude in a single myocyte, many other parameters will participate in the inotropic response to β 3 -AR agonists. One of these is the action potential duration, which is affected not only by β 3 -AR regulation of I Ca,L but also by the effect of the receptor on other ion channels, such as I Ks (51), the rapid component of the delayed rectifier potassium current (I Kr ) (52), the hyperpolarization-activated pacemaker current I f (54), and the cystic fibrosis transmembrane conductance regulator (CFTR) Cl -current (18). Other downstream factors include intracellular Ca 2+ transient and sarcoplasmic reticulum function and the phosphorylation status of key proteins such as phospholamban, ryanodine receptor, and contractile proteins.…”