Review
The ER and ageing II: Calcium homeostasis

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Abstract

Increase in intracellular Ca2+ concentration occurs by Ca2+ influx through the plasma membrane and by Ca2+ release from intracellular stores. The ER is the most important Ca2+ store. Its stress, characterized by the impairment of Ca2+ homeostasis and by the accumulation of misfolded proteins, can be induced by different factors. In turn, it induces defense mechanisms such as unfolded protein response, and when it is severe and prolonged, activation of the apoptotic pathway. Damage to the ER, impairment of its function, and a decreased level of its Ca2+-handling proteins might all play a role in physiological ageing by handicapping the ER stress response. Thus, healthy ageing is accompanied by subtle alterations of Ca2+ homeostasis and signaling, including alterations in the ER Ca2+ load and release. The expression and/or function of ryanodine receptors, IP3 receptors, and SERCA Ca2+ pumps located in the ER membrane, and Ca2+-binding proteins within ER lumen all seem to be affected in aged cells. Data are presented on age-dependent, tissue-specific changes in ER-related Ca2+ homeostasis in skeletal, cardiac and smooth muscles, as well as in the nervous and immune systems. Disturbances of Ca2+ homeostasis and of signaling are potential targets for intervention in aged humans.

Introduction

Intracellular oscillations in Ca2+ ion concentration regulate processes such as proliferation, transcription, contraction, exocytosis, apoptosis, and immune response (reviewed in Carafoli, 2002 and in Berridge et al., 2003). Ca2+ concentration is tightly regulated by multiple Ca2+ channels, pumps, exchangers and buffers. Eukaryotic cells can increase cytoplasmic Ca2+ concentration by influx of these ions through the plasma membrane (PM) and by their release from intracellular stores (Fig. 1). Various Ca2+-permeable channels are present in the PM. In excitable cells, depending on the cell type, voltage-operated Ca2+ channels (VOCCs) (reviewed in Bertolino and Llinas, 1992, and in Felix, 2005) or receptor-activated Ca2+ channels (RACCs) (reviewed in Trebak et al., 2003) predominate. Transient receptor potential channels (TRPCs) are RACCs that are activated by different stimuli, such as intra- and extracellular messengers, chemical, mechanical, and osmotic stress, and by the Ca2+ content of intracellular stores (reviewed in Clapham, 2003). However, RACCs are also present in non-excitable cells, for example, the highly Ca2+-selective arachidonic acid-regulated channels in HEK293, HeLa, COS cell lines and in parotid and pancreatic acinar cells (reviewed in Shuttleworth et al., 2004). Receptor-induced Ca2+ signals lead to the release of Ca2+ from the endoplasmic reticulum (ER) stores, triggering Ca2+ entry through the different PM store-operated channels. Similarly, VOCCs are also expressed in many non-excitable cells (reviewed in Felix, 2005). Highly selective store-operated Ca2+ channels (SOCCs) are present in the PM. Since Ca2+ regulates numerous and distinct cellular processes, stimulus-evoked Ca2+ responses need to be spatially and temporally restricted: Ca2+ influx across the PM or its release from the ER creates microdomains with high local concentrations of Ca2+ (estimated to be in the range of 50–100 μM) (Targos et al., 2005, Kiselyov et al., 2006, McCarron et al., 2006).

The endoplasmic reticulum is an organelle extending throughout all parts of eukaryotic cells. The ER is indispensable for the synthesis, folding, posttranslational modifications and transport of proteins to their target locations (reviewed in Zhang and Kaufman, 2006, and in Görlach et al., 2006). The ER is the most important intracellular Ca2+ store that can accumulate Ca2+ to concentrations of 10–100 mM, while its concentration in the cytoplasm of the resting cell remains within the range of 100–300 nM (reviewed in Ganitkevich, 2003, in Görlach et al., 2006, and in Rossi et al., 2008). Upon stimulation of PM receptors or upon electrical excitation of the PM, the ER releases Ca2+, thus participating in the generation of rapid Ca2+ signals. Since the ER storage capacity is limited, Ca2+ release must be followed by Ca2+ replenishment. Ca2+ movements across the ER membrane are facilitated by three classes of proteins: Ca2+ release channels – inositol-1,4,5-triphosphate (IP3) receptors (IP3Rs) (reviewed in Bezprozvanny, 2005 and in Mikoshiba, 2007) and ryanodine receptors (RyRs) (reviewed in Rossi and Sorrentino, 2002, and in Hamilton, 2005), Ca2+ re-uptake pumps – sarco-endoplasmic reticulum Ca2+-ATPases (SERCAs) (reviewed in East, 2000 and in Periasamy and Kalyanasundaram, 2007), and luminal Ca2+-binding proteins, such as calsequestrin, sarcalumenin, histidine-rich Ca2+-binding protein, calreticulin, etc.

IP3Rs, protein components of Ca2+ release channels present in the ER membrane, are expressed in all mammalian cells. IP3R contains the IP3-binding suppressor domain, IP3-binding domain, and two putative Ca2+-binding sites in its N-terminal part and in its C-terminal channel-forming domain. There are three isoforms of IP3R (IP3R1–3). The channel is composed of four IP3R subunits (Miyakawa et al., 2001, Bosanac et al., 2002; reviewed in Bezprozvanny, 2005). It releases Ca2+ into the cytoplasm in response to IP3 produced by diverse stimuli; however, it is also regulated by other ligands, such as cytoplasmic Ca2+ (reviewed in Foskett et al., 2007). RyRs are large proteins positioned in the ER membrane with a major part of their molecules facing the cytoplasm. Transmembrane and luminal domains constitute only approximately 20% of the RyR mass. RyR tetramers form massive Ca2+ release channels that interact with many accessory proteins. Ca2+-sensing domains (putative EF-hands) are present on both the luminal and the cytoplasmic sides of RyRs. There are three isoforms of RyR known (RyR1–3). RyR1 and RyR2 are mostly expressed in the skeletal and cardiac muscles, respectively, while RyR3 is expressed ubiquitously. The release of Ca2+ from the ER, mediated by RyR channels, is essential for striated muscle contraction and for diverse neuronal functions (Takeshima et al., 1989; reviewed in Hamilton, 2005 and in Laver, 2007). The family of SERCA proteins consists of three isoforms (SERCA1–3) with SERCA2 being evolutionary the oldest and the most widely expressed. In addition, a number of splice variants of these proteins are known: more than 10 different SERCA isoforms have been detected at the protein level (reviewed in East, 2000 and in Periasamy and Kalyanasundaram, 2007). These isoforms exhibit both tissue and temporal specificity. Furthermore, there is evidence showing that different isoforms of SERCA might predominate in various parts of the ER (Liu et al., 2003, Supłat et al., 2004). Their activity is regulated by N-glycosylation, glutathionylation, Ca2+/calmodulin kinase II-dependent phosphorylation, and interaction with other proteins such as phospholamban (PLB) and sarcolipin (SLN) expressed in cardiac and skeletal muscles (reviewed in Strehler and Treiman, 2004, Traaseth et al., 2008).

In the majority of excitable cells, a major route of Ca2+ entry into the cytoplasm are channels located in the PM; they are different types of VOCCs and RACCs. However, intracellular Ca2+ stores, including the ER, also play an important role in signal propagation. A major Ca2+ entry pathway in non-excitable cells is initiated by depletion of Ca2+ from the ER. In fact, growing body of evidence shows that this mechanism plays an important role in excitable cells, too. Several distinct SOCCs are known including the best-studied Ca2+ release-activated channels (CRACs). Concentration of Ca2+ in the lumen of the ER is ‘sensed’ by stromal interaction molecule 1 (STIM1), a protein residing in the ER membrane and containing a single transmembrane domain. Its N-terminus positioned in the lumen of the ER contains the SAM domain, Ca2+-sensing region built of canonical EF-hand, and a ‘hidden’ EF-hand that does not bind Ca2+, but stabilizes the canonical EF-hand (Stathopulos et al., 2008). When the ER Ca2+ content is high, STIM1 molecules are distributed throughout the ER membrane, bind a single Ca2+ ion, and their N-termini are folded. Upon Ca2+ depletion, the Ca2+ ion detaches from the EF-hand of STIM1; this results in partial unfolding of the N-terminus and in the aggregation of STIM1 molecules (Luik et al., 2008, Stathopulos et al., 2008). STIM1 oligomers translocate to the proximity of the PM (Zhang et al., 2005, Liou et al., 2007) and form so-called “punctae”. A fraction of STIM1 is present in the PM (Zhang et al., 2005). Some researchers show that STIM1 translocates to the PM from the ER (Zhang et al., 2005), while others do not observe such phenomenon (Wu et al., 2006). The C-terminal regions of STIM1 molecules activate Ca2+ release-activated Ca2+ modulator 1 (Orai1) proteins that reside in the PM. Each Orai1 molecule possesses four transmembrane domains and its both N- and C-termini are positioned inside the cell (Huang et al., 2006, Gwack et al., 2007). Four Orai1 molecules create the pore-forming subunit of CRAC that opens upon stimulation by STIM1 with the C-terminus of STIM1 and N-terminus of Orai1 participating in this process (Lewis, 2007). This facilitates Ca2+ influx into the cytoplasm, a mechanism called store-operated Ca2+ entry (SOCE). Ca2+ inflow through the PM refills the ER store, enabling it to release Ca2+ in response to a subsequent stimulus. Stromal interaction protein 2 (STIM2) seems to have similar properties as STIM1 (reviewed in Dziadek and Johnstone, 2007), although in the brain it has partially distinct distribution (Skibinska-Kijek et al., unpublished). Some authors suggest that STIM2 has a function distinct from that of STIM1; namely, STIM2 is a feedback regulator that stabilizes basal cytosolic and ER Ca2+ levels (Brandman et al., 2007), a regulator that acts not only on store-dependent, but also on store-independent modes of CRAC channel activation (Parvez et al., 2008).

Analysis of the available data shows that Ca2+ homeostasis is affected in virtually all tissues examined so far with respect to ageing. In this review we focus on tissues in which Ca2+ signaling is indispensable for their major function such is contraction in muscle and signal transduction in nervous system. In each section dedicated to a given tissue we will briefly describe physiological expression and function of the ER-located and ER-interacting proteins involved in the regulation of Ca2+ homeostasis, and then follow with the description of changes observed in the aged cells.

Section snippets

The ER, Ca2+ homeostasis and ageing

Disturbance of ER homeostasis by a range of different factors and ‘toxic’ agents results in ER stress characterized by the accumulation of misfolded proteins and by the impairment of Ca2+ homeostasis. Initially, ER stress induces activation of the defense mechanisms (e.g. unfolded protein response, UPR). However, if stress is severe and long-lasting, the apoptotic cell death pathway might be activated (reviewed in Breckenridge et al., 2003 and in Mattson and Chan, 2003). There is some evidence,

Heart

Heart rhythm is initiated in sinoatrial nodal cells during the late spontaneous diastolic depolarization, by so-called ‘Ca2+ sarcoplasmic reticulum (SR, an equivalent of ER in muscle cells) clock’. The rate and the amplitude of ‘Ca2+ SR clock’ depends on up to 10-fold higher protein kinase A-dependent phosphorylation of proteins, such as PLB and RyR2, in these cells compared to atrial and ventricular myocytes (Vinogradova et al., 2006). The ‘Ca2+ SR clock’ generates spontaneous, periodic Ca2+

Skeletal muscle

Mechanism of skeletal muscle contraction is, in principle, very similar to the mechanism of cardiomyocyte contraction (Dulhunty, 2006). Action potential depolarizing the muscle cell membrane is sensed by ‘voltage sensor’ – DHPR. The residues required for excitation–contraction coupling are localized to the II and III DHPR loops (Haarmann et al., 2003, Kugler et al., 2004). In skeletal muscle, DHPR directly interacts with RyR1 (Block et al., 1988). Activation of DHPR results in a subtle change

Smooth muscle

Activation of smooth muscle cell is initiated by plasma membrane depolarization (through various stimuli); this, in turn, initiates influx of Ca2+ into the sarcoplasm mostly through voltage-dependent channels located in the plasma membrane. Controversy persists regarding the presence of Ca2+-induced Ca2+ entry mechanism in smooth muscle: some researchers failed to detect it, while others were able to show that it exists in some types of smooth muscles (reviewed in Chalmers et al., 2007). DHPRs

Central nervous system

Ca2+ ions are indispensable for a number of functions of nervous system, including regulation of gene expression, proliferation, excitability, release of neurotransmitters, and cell death. In neurons, VOCCs (reviewed in Bertolino and Llinas, 1992) and RACCs such as glutamate receptors (for example N-methyl-d-aspartate (NMDA) receptors in hippocampal CA1 synapses) are the most important Ca2+ channels (reviewed in Cavus and Teyler, 1996, in Verkhratsky and Kirchhoff, 2007, and in Verkhratsky et

Peripheral nervous system

The major source of Ca2+ in peripheral neurons is their influx through VOCCs and RACCs located in the PM (reviewed in Kostyuk, 1989). Ca2+ signal initiated in such a way is sustained by the release of Ca2+ from the SR by the CICR mechanism (reviewed in Verkhratsky, 1996, Usachev and Thayer, 1999). Return to basal Ca2+ level is achieved thanks to the action of Ca2+-buffering proteins and membrane-located pumps and exchangers (reviewed in Pottorf et al., 2002).

As in neurons of the central nervous

Immune system

Proper Ca2+ signaling is crucial for the adequate function of the immune system, as underlined by the fact that the defective store-operated Ca2+ entry and Ca2+ release-activated channels function due to Orai1 mutation result in the development of the hereditary severe combined immune deficiency syndrome (Feske et al., 2006). Activation of T lymphocytes by, for example, antigens and mitogens, results in the increase of cytoplasmic Ca2+ concentration (Ullman et al., 1990; reviewed in Guse, 1998,

The ER Ca2+ handling in aged tissues and interventions to improve the ER Ca2+ homeostasis and signaling

Healthy ageing is accompanied by subtle alterations of Ca2+ homeostasis and signaling in the cell. Detailed analysis of the expression and function of Ca2+ channels located in the ER membrane shows that the SERCA amount and activity usually decrease with age in different cell types, while age-related RyR and IP3R alterations are not uniform and depend on the cell type. Ageing is associated with signs of damage to many proteins including the Ca2+-handling proteins: excessive oxidation and

Summary and conclusions

In this review we describe the data regarding the ER Ca2+ dysregulation in different tissues that seem to be associated with ageing. To look for common age-related changes and to identify the changes that are specific to a given tissue, we summarized the available pieces of information in Table 1. The major conclusion is that almost all components of the ER machinery analyzed so far (RyR, IP3R, SERCA, and some luminal ER Ca2+-binding proteins), that play a role in the maintenance of Ca2+

Acknowledgements

This work was supported by PBZ-MEiN-9/2/2006 (K143/P01/2007/1) grants to MP-K from the Polish Ministry of Education and Science, by statutory funds from the Nencki Institute of Experimental Biology (JK) and by Polish–German grant to JK (P-N/001/2006). We thank Dr. Lukasz Bojarski and Dr. Pawel Pomorski for critically reading the manuscript.

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