Elsevier

Cell Calcium

Volume 38, Issues 3–4, September–October 2005, Pages 291-302
Cell Calcium

Modulating sarco(endo)plasmic reticulum Ca2+ ATPase 2 (SERCA2) activity: Cell biological implications

https://doi.org/10.1016/j.ceca.2005.06.033Get rights and content

Abstract

Of the three mammalian members belonging to the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) family, SERCA2 is evolutionary the oldest and shows the most wide tissue-expression pattern. Two major SERCA2 splice variants are well-characterized: the muscle-specific isoform SERCA2a and the housekeeping isoform SERCA2b. Recently, several interacting proteins and post-translational modifications of SERCA2 were identified which may modulate the activity of the Ca2+ pump. This review aims to give an overview of the vast literature concerning the cell biological implications of the SERCA2 isoform diversity and the factors regulating SERCA2. Proteins reported to interact with SERCA2 from the cytosolic domain involve the anti-apoptotic Bcl-2, the insulin receptor substrates IRS1/2, the EF-hand Ca2+-binding protein S100A1 and acylphosphatase. We will focus on the very particular position of SERCA2 as an enzyme functioning in a thin, highly fluid, leaky and cholesterol-poor membrane. Possible differential interactions of SERCA2b and SERCA2a with calreticulin, calnexin and ERp57, which could occur within the lumen of the endoplasmic reticulum will be discussed. Reported post-translational modifications possibly affecting pump activity involve N-glycosylation, glutathionylation and Ca2+/calmodulin kinase II-dependent phosphorylation. Finally, the pronounced vulnerability to oxidative damage of SERCA2 appears to be pivotal in the etiology of various pathologies.

Introduction

The endoplasmic reticulum (ER) appears to be one of the most important signal-transducing organelles within the cell activating a multitude of cell functions by releasing Ca2+, and shutting them down by reuptake via the sarco/endoplasmic reticulum Ca2+-transport ATPases (SERCA).

In mammals, three different SERCA genes (human nomenclature ATP2A1-3) each encode at least two different protein isoforms, which result from tissue-dependent alternative splicing of the transcripts. The well-regulated developmental and tissue-specific expression pattern of the different SERCA isoforms suggests that each isoform is adapted to cell-specific functions. SERCA1a and SERCA1b splice variants are, respectively, expressed in adult and neonatal fast-twitch skeletal muscle [1]. Transcripts of the ATP2A2 gene translate to the SERCA2a and SERCA2b isoforms. SERCA2b is found in the ER of most cell types and is considered the housekeeping isoform. The muscle-specific isoform SERCA2a is expressed in the sarcoplasmic reticulum (SR) of the heart and slow-twitch skeletal muscle [2], [3]. ATP2A3 is expressed in a limited set of non-muscle cells and encodes a number of low-Ca2+-affinity SERCA3 isoforms. In humans, six different splice variants of SERCA3 are known (SERCA3a–f) [4], [5].

In this brief review, we aim to give an overview of recent advances in the rapidly growing field of factors modulating SERCA2's activity. First, we will focus on the two major protein isoforms of SERCA2, i.e. SERCA2a and SERCA2b and the implications of their functional differences for cellular Ca2+ homeostasis. A second part of the review will be devoted to the literature on putative interaction partners of SERCA2, the existing controversies and unanswered questions. Finally, the cell biological implications of post-translational modifications affecting SERCA2's activity will be addressed.

Section snippets

SERCA2 isoform diversity

SERCA2 is by far the most widespread of all SERCA isoforms. It is also evolutionary the oldest. Characterization of the 3′-end of the ATP2A2 gene revealed the presence of four optional exons (exons 22–25), which can be alternatively processed, resulting in four distinct classes of mRNA (classes 1–4). Class 1 mRNA encodes the SERCA2a isoform, whereas classes 2–4 differ only in their 3′-untranslated region and encode the SERCA2b protein [6], [7], [8]. Recently, mRNA traces of a new SERCA2 isoform

B cell lymphoma 2 (Bcl-2) protein and apoptosis

Proteins encoded by the Bcl-2 gene family play a key role in the regulation of apoptosis by exerting either pro-apoptotic or anti-apoptotic effects. Bcl-2, the founding member of the family, is anti-apoptotic. It is targeted to both the outer mitochondrial membrane and the membranes of the ER via membrane insertion of a COOH-terminal hydrophobic domain. This targeting mechanism thus requires a post-translational mechanism of membrane insertion. However, Bcl-2 is also expressed in low abundance

Glycosylation

SERCA2b contains a consensus N-glycosylation site (N1036-X-S1038 in rat SERCA2b, or N1035-X-S1037 in human SERCA2b) in its extended C-terminus facing the ER lumen, which is absent in SERCA2a (Fig. 1) [85]. Based on studies in X. laevis oocytes, it was proposed that the functional differences between SERCA2a and SERCA2b are due to an interaction of CRT or CLNX via their lectin domain with the putative glycosylated residue of SERCA2b [67], [70]. Mutation of either N1036 or S1038 to Ala disrupts

Final remarks

The interaction of the Ca2+-release channels found in the ER or SR (InsP3 receptor and RyR) with numerous protein- and non-protein factors or their regulation by post-translational modifications is already well-documented. Like for InsP3 receptor and RyR, now also SERCA2 emerges as a focus for regulatory interactions. However, due to its smaller size and the requirement to undergo major conformational changes during its enzymatic cycle, formation of a macromolecular SERCA complex is probably

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