The SarcoEndoplasmic Reticulum Calcium ATPase

Abstract

The calcium pump (a.k.a. Ca-ATPase or SERCA) is a membrane transport protein ubiquitously found in the endoplasmic reticulum (ER) of all eukaryotic cells. As a calcium transporter, SERCA maintains the low cytosolic calcium level that enables a vast array of signaling pathways and physiological processes (e.g. synaptic transmission, muscle contraction, fertilization). In muscle cells, SERCA promotes relaxation by pumping calcium ions from the cytosol into the lumen of the sarcoplasmic reticulum (SR), the main storage compartment for intracellular calcium. X-ray crystallographic studies have provided an extensive understanding of the intermediate states that SERCA populates as it progresses through the calcium transport cycle. Historically, SERCA is also known to be regulated by small transmembrane peptides, phospholamban (PLN) and sarcolipin (SLN). PLN is expressed in cardiac muscle, whereas SLN predominates in skeletal and atrial muscle. These two regulatory subunits play critical roles in cardiac contractility. While our understanding of these regulatory mechanisms are still developing, SERCA and PLN are one of the best understood examples of peptide-transporter regulatory interactions. Nonetheless, SERCA appeared to have only two regulatory subunits, while the related sodium pump (a.k.a. Na, K-ATPase) has at least nine small transmembrane peptides that provide tissue specific regulation. The last few years have seen a renaissance in our understanding of SERCA regulatory subunits. First, structures of the SERCA-SLN and SERCA-PLN complexes revealed molecular details of their interactions. Second, an array of micropeptides concealed within long non-coding RNAs have been identified as new SERCA regulators. This chapter will describe our current understanding of SERCA structure, function, and regulation.

Regulating the regulator: intramembrane proteolysis of vesicular trafficking proteins and the SERCA regulator phospholamban

“…The reuptake of Ca 2+ by the SERCA transporter in the sarco‐endoplasmic reticulum (SER) has profound effects on muscle contraction and regulation, but also on signaling mechanisms and cell differentiation. Phospholamban is a 52 amino acid single‐pass membrane protein that regulates the Ca 2+ affinity of SER Ca 2+ ‐ATPase SERCA . SPPL2c and phospholamban colocalized in the ER, and expression of SPPL2c led to depletion of phospholamban .…”

Polyglutamine-expanded androgen receptor disrupts muscle triad, calcium dynamics and the excitation-contraction coupling gene expression program

“…Upon arrival of the action potential at the NMJ, membrane depolarization leads to a conformational change in dihydropyridine receptors (DHPRs) and RYR, leading to release of Ca ++ from the SR to the myoplasm to trigger muscle contraction. Ca ++ transients in the myoplasm are rapidly followed by Ca ++ reuptake through the SR Ca ++ -ATPase (SERCA) 1 and SERCA2, to stop contraction and relax myofibers (45). The magnitude of Ca ++ transients is regulated by several buffering proteins, including parvalbumin (PV) in the cytosol (46), and calsequestrin 1 (CASQ1) and CASQ2 in the SR (47).…”

“…The magnitude of Ca ++ transients is regulated by several buffering proteins, including parvalbumin (PV) in the cytosol (46), and calsequestrin 1 (CASQ1) and CASQ2 in the SR (47). Another key player in Ca ++ dynamics is the SERCA inhibitor, sarcolipin (SLN) (45). Our observation that time to contract and relax was extended in AR100Q mice (Figure 2C and F) prompted us to test whether aberrant handling of Ca ++ dynamics contributes to defects in intrinsic muscle force generation.…”

High throughput screening to identify inhibitors of the type I interferon – major histocompatibility complex class I pathway in skeletal muscle

“…Compounds that were active at decreasing MHC class I protein but far less effective on mRNA were inhibitors for: BRD4, proteasome, HSP90, Na+/K+ ATPase, and SERCA. Na+/K+ ATPase and SERCA are important for endoplasmic reticulum function (Patel, 2016; Primeau et al, 2018), through which nascent MHC class I protein is folded and processed, so inhibiting their function appears to decrease MHC class I protein production without affecting its transcription.…”