Investigating the role of PKA type I in the heart

Abstract

Norepinephrine and epinephrine provide the most powerful stimulation of cardiac function through activation of β-adrenergic receptors and the cAMP-dependent protein kinase (PKA). The PKA holoenzyme consists of a dimer of regulatory (R) subunits that binds and inhibits two catalytic subunits (C). Two types of PKA are expressed in the heart, type I and type II, differing by their R subunit, RIα and RIIα. Whereas PKA type II plays an important role in the regulation of cardiac contractility, the role of the PKA type I is little understood. To investigate the role of PKA type I in the adult heart. The cardiac phenotype of two mouse models was investigated. The first is a cardiac-specific and conditional knock-out of RIα (RIα-KO) which leads to a constitutive activation of PKA type I in the heart. The second is a knock-in mutation in the cAMP-binding site of RIα leading to a higher activation threshold for PKA type I (ADO-MUT). Echocardiography shows that young RIα-KO mice have an increased ejection fraction (EF) associated with greater phosphorylation of the key players of excitation-contraction coupling but no change in heart rate (HR). Besides, with age, these mice develop cardiac hypertrophy, dilatation and die from heart failure (HF). In contrast, young ADO-MUT mice have a slightly decreased EF and HR, and do not develop HF with age. In RIα-KO mice, gene and RIα protein deletion were not efficient in the sino-atrial node (SAN). Thus, a third model was developed in which RIα can be specifically and conditionally invalidated in the SAN and conduction system by the use of a HCN4 promoter to investigate the role of PKA type I in cardiac automatism. Thus far, our results indicate a previously unsuspected role of PKA type I in cardiac contraction and possibly also in automatism.