PDE4DIP in health and diseases

Abstract

Cyclic-AMP (cAMP), the first second messenger to be identified, is synthesized, and is universally utilized as a second messenger, and plays important roles in integrity, and function of organs, including heart. Through its coupling with other intracellular messengers, cAMP facilitates excitation-contraction coupling, increases heart rate and conduction velocity. It is degraded by a class of enzymes called cAMP-dependent phosphodiesterase (PDE), with PDE3 and PDE4 being the predominant isoforms in the heart. This highly diverse class of enzymes degrade cAMP and through anchoring proteins generates dynamic microdomains to target specific proteins and control specific cell functions in response to various stimuli. The impaired function of the anchoring protein either by inherited genetic mutations or acquired injuries results in altered intracellular targeting, and blunted responsiveness to stimulating pathways and contributes to pathological cardiac remodeling, cardiac arrhythmias and reduced cell survival. Recent genetic studies provide compelling evidence for an association between the variants in the anchoring protein PDE4DIP and atrial fibrillation, stroke, and heart failure.

Fig. 1.

Schematic figure demonstrating the microdomain of PDE4D, PDE4DIP, cAMP on Golgi apparatus. βAR denotes beta adrenergic, PDE, Phosphodiesterases, PDE4DIP, Phosphodiesterase 4D Interacting Protein.

Fig. 2.

PDE4DIP mutations in familial AF kindreds. Only Coiled coil domains 1, 3, 8 and 12 are shown.