REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Background Heart failure is a complex syndrome characterized by cardiac contractile impairment with high mortality. Defective intracellular Ca 2+ homeostasis is the central cause under this scenario and tightly links to ultrastructural rearrangements of sarcolemmal transverse tubules and the sarcoplasmic reticulum ( SR ); however, the modulators of the SR architecture remain unknown. The SR has been thought to be a specialized endoplasmic reticulum membrane system. Receptor accessory proteins ( REEP s)/ DP 1/Yop1p are responsible for shaping high‐curvature endoplasmic reticulum tubules. This study aimed to determine the role of REEP s in SR membrane shaping and thus cardiac function. Methods and Results We identified REEP 5 (receptor accessory protein 5) as more highly expressed than other REEP members in adult rat ventricular myocardium, and it was downregulated in the failing hearts. Targeted inactivation of REEP 5 in rats specially deformed the cardiac SR membrane without affecting transverse tubules, and this was visualized by focused ion beam scanning electron microscopy–based 3‐dimensional reconstruction. Accordingly, simultaneous recordings of depolarization‐induced Ca 2+ currents and Ca 2+ transients in REEP 5 ‐null cardiomyocytes revealed normal L‐type Ca 2+ channel currents but a depressed SR Ca 2+ release. Consequently, the excitation–contraction coupling gain of cardiomyocytes and consequent cardiac contractility were compromised. REEP 5 deficiency did not alter the expression of major proteins involved in Ca 2+ handling in the heart. Conclusions REEP 5 modulates cardiac function by shaping the SR . REEP5 defect deforms the SR architecture to depress cardiac contractility. REEP 5‐dependent SR shaping might have potential as a therapeutic target for heart failure.