14‐3‐3 proteins: Regulators of cardiac excitation–contraction coupling and stress responses

14‐3‐3 proteins are highly conserved proteins that regulate numerous cellular processes mostly through phosphorylation‐dependent protein–protein interactions. In the heart 14‐3‐3 proteins play critical roles in cardiac conduction pathways, excitation–contraction (EC) coupling, development and stress responses. This review summarizes the current understanding of cardiac 14‐3‐3 regulation and function, with particular emphasis on its role in ion channel regulation and β‐adrenergic signalling. We discuss how 14‐3‐3 proteins act through three main mechanisms – masking, clamping, and scaffolding – to regulate target proteins, including Cx43, Ca V 1.2, Na V 1.5, and various potassium channels. The seven mammalian 14‐3‐3 isoforms display distinct but overlapping functions, with tissue‐specific expression patterns and isoform‐specific regulation through phosphorylation and dimerization. Recent work has revealed 14‐3‐3's importance in cardiac development and stress responses, where it generally serves a cardioprotective role. However in some pathological contexts such as ischaemia–reperfusion injury, 14‐3‐3 can be detrimental. We highlight emerging themes in cardiac 14‐3‐3 biology, including its role in prolonging β‐adrenergic signalling. Understanding the complex regulation of cardiac 14‐3‐3 and its numerous targets presents both opportunities and challenges for therapeutic development. image