G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies sick sinus syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Ca(v)1.3 Ca2+ channels (Ca(v)1.3(-/-)) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K+ channel (I-KACh) could rescue SSS and heart block in Cav1.3(-/-)mice. We found that genetic inactivation of I-KACh abolished SSS symptoms in Cav1.3(-/-) mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of I-KACh either in Cav1.3(-/-) mice or following selective inhibition of Ca(v)1.3-mediated L-type Ca2+ (I-Ca,I- L) current in vivo. Ablation of I-KACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from I-KACh suppression achieved by gene therapy or selective pharmacological inhibition.