Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an I_Ks transgenic mouse

Abstract

Inherited gain-of-function mutations of genes coding for subunits of the heart slow potassium (I Ks ) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that β-adrenergic receptor (β-AR)-mediated regulation of the I Ks channel, a natural gain-of-function pathway, can also lead to AF. Using a transgenic I Ks channel mouse model, we studied the role of the channel and its regulation by β-AR stimulation on atrial arrhythmias. In vivo administration of isoprenaline (isoproterenol) predisposes I Ks channel transgenic mice but not wild-type (WT) littermates that lack I Ks to prolonged atrial arrhythmias. Patch-clamp analysis demonstrated expression and isoprenaline-mediated regulation of I Ks in atrial myocytes from transgenic but not WT littermates. Furthermore, computational modelling revealed that β-AR stimulation-dependent accumulation of open I Ks channels accounts for the pro-arrhythmic substrate. Our results provide evidence that β-AR-regulated I Ks channels can play a role in AF and imply that specific I Ks deregulation, perhaps through disruption of the I Ks macromolecular complex necessary for β-AR-mediated I Ks channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia.

Abscisic acid regulation of guard-cell K + and anion channels in Gβ- and RGS-deficient Arabidopsis lines

“…In guard cells, PLC and PLD appear to operate in the same ABA-signaling cascade (45), and phosphatidic acid (PA), the product of PLD activity, is another attractive candidate regulator: PA inhibits guard-cell K in currents (45), and PLD is ABA-activated (45) and regulated by G␣ in guard cells (46). In addition, one class of Shaker-like channels, the KCNQ channels, whose mutation is associated with genetic diseases including long QT syndrome and atrial arrhythmias (47), displays modulation via a G s -dependent cascade, including activation by PtdInsP 2 (47,48). On a sequence homology basis, the guard cell K in channels, despite evincing inward rectification, are similar to metazoan Shaker K ϩ channels (27).…”

Cyclic Adenosine Monophosphate Phosphodiesterase Type 4 Protects Against Atrial Arrhythmias

“…PDE4D3 was found in macromolecular signaling complexes regulating 2 major players of excitation-contraction coupling in rodent heart: the slow delayed rectifier K ϩ current (16) and the ryanodine receptor RyR2 (17). Interestingly, inhibition of PDE4D leads to an increased PKA activation of the slow delayed rectifier K ϩ current (16), which can contribute to AF (18). Here we found that PDE4D was the dominant member of the PDE4 family expressed in human atrium.…”

Overlapping Cardiac Phenotype Associated with a Familial Mutation in the Voltage Sensor of the KCNQ1 Channel

“…Common to some of these mutations in I Ks subunits is a gain-of-function phenotype based mainly on alteration of channel gating and altered functional -subunit modulation upon heterologous expression experiments. Although, care has to be taken to interpret effects on KCNQ1/KCNE channel features in heterologous expression [26], the gainof-function phenotypes may allow for the development of AF as a result of increased I Ks and resultant action potential shortening [27,28]. Very recently, a combined phenotype of LQTS and atrial fibrillation was reported for carriers of the mutation R231C [29].…”