Dataset Information

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

ABSTRACT: BACKGROUND:Heart failure is a complex syndrome characterized by cardiac contractile impairment with high mortality. Defective intracellular Ca2+ 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 Ca2+ currents and Ca2+ transients in REEP5-null cardiomyocytes revealed normal L-type Ca2+ channel currents but a depressed SR Ca2+ 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 Ca2+ 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.

SUBMITTER: Yao L

PROVIDER: S-EPMC5850239 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Yao Lei L Xie Duanyang D Geng Li L Shi Dan D Huang Jian J Wu Yufei Y Lv Fei F Liang Dandan D Li Li L Liu Yi Y Li Jun J Chen Yi-Han YH

Journal of the American Heart Association 20180203 3

<h4>Background</h4>Heart failure is a complex syndrome characterized by cardiac contractile impairment with high mortality. Defective intracellular Ca<sup>2+</sup> 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 acces ...[more]

PMID: 29431104

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Project description:Cardiac sarcoplasmic reticulum (SR) plays a central role in cellular Ca homeostasis, as does endoplasmic reticulum (ER) in the nonmuscle cell. The importance of SR Ca-handling function has led to detailed understanding of Ca-release and re-uptake protein complexes, but relatively little information regarding other known ER functions. We isolated cardiac membranes based upon their ability to efficiently accumulate Ca by the SR,ER-ATPase (SERCA-positive membranes), a process known to produce two characteristic SR membrane fractions: those enriched in known junctional SR markers, and those enriched in proteins originating from classic ER subdomains. Using standard proteomic techniques, we determined the SR proteins in three membrane preparations: 1) the highest-density SERCA-positive microsomes (HighSR); 2) the slightly less dense SERCA-positive microsomes that are constrained by a ryanodine-dependent leak (MedSR); and the original crude cardiac microsomes. Only a third of all crude microsomal proteins in heart were enriched in SERCA-positive membranes at least two fold. This protocol completely excluded known contractile, mitochondrial, sarcolemmal, and other major microsomal proteins, producing a far cleaner preparation of SR. Each SERCA-positive protein was distributed between HighSR and MedSR membrane vesicles in accordance with relative densities of SERCA2a versus ryanodine receptor. The distributions reinforced past findings on the distributions for several of the major known proteins. When combined with values for relative abundance, and enrichment over crude membranes, our protocol conveniently and effectively exposed multiple domains of the cardiac ER/SR. Most of the highly enriched and abundant cardiac SR/ER proteins represent proteins that have received little research attention. The data generate a useful quantitative analysis of intracellular membrane structure and function within cardiomyocytes, and may provide a reliable way of gauging broader changes in cardiac SR.

Dataset Information

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

Publications

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

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