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 (REEPs)/DP1/Yop1p are responsible for shaping high‐curvature endoplasmic reticulum tubules. This study aimed to determine the role of REEPs in SR membrane shaping and thus cardiac function. METHODS AND RESULTS: We identified REEP5 (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 REEP5 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 REEP5‐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. REEP5 deficiency did not alter the expression of major proteins involved in Ca(2+) handling in the heart. CONCLUSIONS: REEP5 modulates cardiac function by shaping the SR. REEP5 defect deforms the SR architecture to depress cardiac contractility. REEP5‐dependent SR shaping might have potential as a therapeutic target for heart failure.