Relevance of KCNJ5 in Pathologies of Heart Disease

Abstract

Abnormalities in G-protein-gated inwardly rectifying potassium (GIRK) channels have been implicated in diseased states of the cardiovascular system; however, the role of GIRK4 (Kir3.4) in cardiac physiology and pathophysiology has yet to be completely understood. Within the heart, the KACh channel, consisting of two GIRK1 and two GIRK4 subunits, plays a major role in modulating the parasympathetic nervous system’s influence on cardiac physiology. Being that GIRK4 is necessary for the functional KACh channel, KCNJ5, which encodes GIRK4, it presents as a therapeutic target for cardiovascular pathology. Human variants in KCNJ5 have been identified in familial hyperaldosteronism type III, long QT syndrome, atrial fibrillation, and sinus node dysfunction. Here, we explore the relevance of KCNJ5 in each of these diseases. Further, we address the limitations and complexities of discerning the role of KCNJ5 in cardiovascular pathophysiology, as identical human variants of KCNJ5 have been identified in several diseases with overlapping pathophysiology.

Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old

“…Given that most ion channels are present in both atrial and ventricular myocardium, LQTS may also impact atrial electrophysiology and be associated with an increased risk of AF [Table 1] [34][35][36][37]. In a large group of LQTS patients, a significant association between the LQT3 genotype and an increased risk of early AF has been observed [38][39][40][41][42][43].…”

The W101C KCNJ5 Mutation Induces Slower Pacing by Constitutively Active GIRK Channels in hiPSC-Derived Cardiomyocytes

“…Currently, 31 disease-causing variants in the KCNJ5 gene are known to date. Potential heart disease variants in KCNJ5 have been described and may be causative for long QT syndrome, Andersen-Tawil syndrome, atrial fibrillation, short QT syndrome, or unspecified events like sudden cardiac arrest or sudden unexpected death [21][22][23][24][25][26][27][28][29]. However, due to the small number of cases and mostly missing functional data, KCNJ5 is not a proven gene for the respective diseases.…”