Natural Polyphenols as SERCA Activators: History
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Contributor:
Jana Viskupicova
,
Petronela Rezbarikova

Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is a key protein responsible for transporting Ca2+ ions from the cytosol into the lumen of the sarco/endoplasmic reticulum (SR/ER), thus maintaining Ca2+ homeostasis within cells. Accumulating evidence suggests that impaired SERCA function is associated with disruption of intracellular Ca2+ homeostasis and induction of ER stress, leading to different chronic pathological conditions. Therefore, appropriate strategies to control Ca2+ homeostasis via modulation of either SERCA pump activity/expression or relevant signaling pathways may represent a useful approach to combat pathological states associated with ER stress. Natural dietary polyphenolic compounds, such as resveratrol, gingerol, ellagic acid, luteolin, or green tea polyphenols, with a number of health-promoting properties, have been described either to increase SERCA activity/expression directly or to affect Ca2+ signaling pathways.

  • Ca2+ signaling
  • ER stress
  • SERCA
  • polyphenols

1. Introduction

Calcium (Ca2+) is one of the most important regulators of cell survival/death processes. Aberrations in Ca2+ homeostasis have been linked to the development of various pathophysiological conditions, such as cardiovascular diseases [1][2], diabetes [3][4], cancer [5], neurodegenerative diseases [6][7], and skeletal muscle pathologies [8]. Intracellular Ca2+ concentrations [(Ca2+)i] must be maintained within very low concentrations (~10–100 nmol/L), which are regulated by a number of Ca2+ transport systems, such as pumps and channels [9]. The most important amongst them are the sarco/endoplasmic reticulum (SR/ER) Ca2+-ATPase (SERCA) pumps, which transport Ca2+ ions from the cytosol into the SR/ER ([(Ca2+)SR/ER]~100 to 800 μmol/L) in an ATP-dependent manner [10], thus maintaining a steep concentration gradient of Ca2+ across the membrane [11]. SERCA pumps are coded by three genes (ATP2a1, ATP2a2, and ATP2a3), which generate several distinct tissue-specific SERCA isoforms (SERCA1–3) through alternative splicing [12]. Currently, more than 14 tissue-specific SERCA mRNA splice variants and their corresponding proteins have been discovered [13]. Impaired Ca2+ uptake into cardiac, vascular, and skeletal cells, or decreased SR/ER Ca2+ content, is associated with downregulation/reduced activity of the respective SERCA isoforms. These changes further intervene in calcium-release channels (ryanodine receptors (RyRs) and inositol-1,4,5-triphosphate receptors (IP3Rs)) and plasma membrane Ca2+-influx channels, such as transient receptor potential canonical channels and calcium-release-activated calcium channels (ORAI), causing disruption of intracellular Ca2+ homeostasis [14].
Under certain pathophysiological conditions—including Ca2+ homeostasis imbalance, increased secretory load, energy deprivation, impaired redox homeostasis, viral infections, cytotoxicity, inflammation, and mutations [15][16]—unfolded and misfolded proteins may be accumulated in the ER, activating a condition called ER stress. In order to restore ER homeostasis, cells activate secondary adaptive events known as unfolded protein responses, along with related signaling pathways, such as reduced protein loading into the ER, translational attenuation, and correction of protein folding [17]. However, if the stress is persistent, the processes of either apoptotic cell death or autophagy are triggered. The inositol-requiring enzyme 1 with c-Jun NH2-terminal kinase (JNK) and eukaryotic initiation factor 2 alpha with C/EBP homologous protein signaling pathways belong to the main paths of ER stress, which are modulated by different factors involving injured Ca2+ homeostasis [18]. ER stress has been recognized to be linked to various disease pathogeneses, including obesity, diabetes, metabolic syndrome, neurodegenerative diseases, and cancer [19][20]. Increasing evidence suggests that a critical role in triggering ER stress is attributed to reduced SERCA2b function, while restoration of SERCA2b leads to the relief of ER stress [21]. Overexpression of SERCA2a by gene therapy has been successfully used in clinical models of heart failure [22].
SERCA function is modulated by various physiological processes and endogenous factors. Primarily, the activity of SERCA pumps is regulated by two small endogenous proteins: phospholamban (PLB) and sarcolipin (SLN), expressed in cardiac and skeletal muscles, respectively. They bind to the regulatory site in SERCA and, thus, reduce the apparent affinity of SERCA1a and SERCA2a for Ca2+, in the case of SLN and PLB, respectively [23], although both SLN and PLB may be involved in the modulation of either SERCA isoform [24]. Recently, dwarf open reading frame (DWORF) has been reported as a new endogenous regulator of SERCA [25]. DWORF acts as a direct activator of SERCA, removing PLB as an inhibitor of SERCA and, thus, increasing its turnover rate [26]. ER Ca2+ dynamics are also controlled by anti- and pro-apoptotic proteins, such as Bcl-2 family members and protein p53, respectively. Studies demonstrate that Bcl-2 overexpression reduces ER Ca2+ levels by inhibiting SERCA2 [27], while the tumor suppressor p53 stimulates SERCA activity, resulting in ER Ca2+ overload [28][29]. Additionally, various post-translational modifications and protein–protein interactions of SERCA have been described, leading to enhancement of SERCA activity and Ca2+ uptake [30].

2. Intracellular Ca2+ Regulation: The Role of SERCA

The endoplasmic reticulum and mitochondria are the main regulators of intracellular Ca2+ homeostasis, which is important to maintain a variety of cellular functions. This requires a complex interplay of different Ca2+ transporters, along with Ca2+-sensing and -buffering proteins, channels, receptors, and their regulators. The low [Ca2+]i is maintained due to the action of the plasma membrane Ca2+-ATPase (PMCA) and Na+/Ca2+-exchanger (NCX), which are responsible for the extrusion of Ca2+ from the cell. Upon elevated [Ca2+]i, the SERCA pump is activated to maintain the required [Ca2+]i by sequestering Ca2+ from the cytosol into the ER [31]. Calcium-permeable channels located on the plasma membrane regulate the entry of Ca2+ into the cell. These include voltage-gated calcium channels (VGCCs), which respond to membrane depolarization; receptor-operated channels (ROCs), which are activated by the interaction with ligands; and store-operated calcium channels (SOCs), which are stimulated by the depletion of internal Ca2+ stores. The inositol-1,4,5-triphosphate receptor (IP3R) and the ryanodine receptors (RyRs) are the main players in mediating the release of Ca2+ from the internal stores. Inositol-1,4,5-triphosphate activates IP3R, triggers the release of Ca2+ from stores, and further increases IP3R’s sensitivity to Ca2+ [32]. Store-operated Ca2+ entry (SOCE) significantly contributes to the dynamics of Ca2+ in cells. This Ca2+ signaling pathway is activated upon Ca2+ store depletion; consequently, the ER Ca2+-sensing stromal interaction molecules (STIM1 and STIM2) oligomerize, move to the ER membrane, and bind to the calcium-release-activated calcium (CRAC) channel proteins ORAI1, ORAI2, and ORAI3, located in the plasma membrane, allowing pore opening for Ca2+ to enter the cell [33]. Some members of TRPC (transient receptor potential canonical) channels may also contribute to a store-operated current [34]. Inter-organelle communication between the ER and mitochondria is mediated via mitochondria-associated ER membranes (MAMs) in a highly organized manner. There is a diverse group of several critical proteins involved in ER–mitochondria tethering—especially mitofusin 2, responsible for bridge formation between mitochondria and the ER; the interaction of IP3R with voltage-dependent anion channel 1; the mitochondrial Ca2+ uniporter (MCU) complex, involved in coupling between cytosolic/MAM Ca2+ signaling and the activation of key dehydrogenase enzymes for energy generation; and others, as reviewed in [35].
SERCA pumps, together with PMCAs and NCXs, are among the most important regulators responsible for restoring low resting [Ca2+]i. In certain tissues, SERCA sequesters more than 70% of the cytosolic Ca2+ [23]; therefore, it plays a crucial role in maintaining intracellular Ca2+ homeostasis. The primary structures of SERCAs are highly conserved, and individual SERCA isoforms possess a high percentage of sequence homology. Functional differences between SERCA isoforms consist of their affinity for Ca2+ (2b > 2a = 1 > 2c > 3) and their Ca2+ transport turnover rates [13]. Individual SERCA isoforms are tissue-specific, and the impairment in their regulation has been associated with various disease states, as shown in Table 1.
Table 1. The pathophysiological roles of SERCAs in human diseases.
SERCA
Isoform		 Tissue Distribution Disease/Complication SERCA
Activity/Expression		 Reference
SERCA1a Adult fast-twitch
skeletal muscle		 Brody’s disease ↓/↓ [12][36]
SERCA1b Fetal fast-twitch
skeletal muscle		 Myotonic dystrophy type 1 ↓/↑ [12][37]
SERCA2a Slow twitch skeletal muscle, cardiac muscle, smooth muscle cells Heart failure
Cardiac hypertrophy
Diabetic cardiomyopathy
Vascular complications
Early type 2 diabetes		 ↓/↓
-/↓
↓/↓
↓/↓
-/↑		 [12][13][38][39]
SERCA2b All tissues (muscle and non-muscle cells) Darier’s disease
Type 1 and 2 diabetes
Cancer
Neurodegenerative diseases		 ↓/↓
↓/↓
-/↓
↓/↓↑		 [12][36][40][41][42]
SERCA2c Epithelial, mesenchymal, and hematopoietic cells;
monocytes		 Cardiomyopathy -/↑ [28][36][43]
SERCA2d Skeletal muscle Myotonic dystrophy type 1 -/↓ [37]
SERCA3a-f Non-muscle
tissues		 Type 2 diabetes
Type 1 diabetes
Cardiomyopathy
Cancer		 -/↓
-/SERCA3b↑
-/SERCA3f↑
-/↑↓		 [39][41][43]
Since the decreased [Ca2+]ER, rather than the increased [Ca2+]i, triggers apoptosis, it has been suggested that maintaining ER Ca2+ homeostasis via ER-localized pumps and channels represents a primary stimulus in triggering mechanisms leading to aberrations of intracellular Ca2+ homeostasis, as well as to the onset of ER-stress-related diseases [39]. These changes are very much dependent on the cell type and the disease model studied. SERCAs, together with STIM1 and ORAI1, contribute to capacitative Ca2+ entry, which is responsible for refilling of the SR/ER stores, with Ca2+ entering cells via activated SOCs [44]. Moreover, the involvement of TRPC1 was reported to contribute to the SOCE pathway in skeletal muscle [45]. The SERCA1 isoform is regulated by STIM1 through direct binding to SERCA1 via the C-terminal part; thus, STIM1 is involved in maintaining SERCA1 activity [46]. In human platelets, SERCA2b and SERCA3 are responsible for the direct regulation of SOCE via the hTRPC1 channel [47], demonstrating strong interplay between SOCE-related proteins and SERCAs. Under conditions of ER stress, the stimulatory interaction between STIM1 and SERCAs was found to be impaired [48]. Defective Ca2+ loading into the SR/ER caused by SERCA dysfunction may be partially compensated by other regulatory mechanisms, such as extrusion of Ca2+ via PMCAs and NCXs, uptake of Ca2+ into the mitochondria or Golgi apparatus, or upregulation of TRPC1 [36]. However, if cellular adaptive mechanisms directed towards balancing Ca2+ homeostasis fail, multiple ER stress-related pathologies can be induced.

3. Pharmacological Activation of SERCA by Polyphenols

Pharmacological activation of SERCA can reduce ER stress, and may therefore represent a promising therapeutic approach for the treatment of diabetes, metabolic disorders,
cardiovascular diseases (especially heart failure), and neuropathological conditions; alternatively, induction of ER stress by polyphenols may contribute to cancer treatment. Natural polyphenols are able to specifically modulate Ca2+ homeostasis and Ca2+ signaling pathways via SERCA. Polyphenols can affect SERCA by direct binding [71], followed by subsequent changes in its structure and activity. In addition, indirect mechanisms may also lead to alterations in SERCA expression and/or activity. Polyphenol-mediated conformational alterations in either the ATP-binding or Ca2+-binding sites of SERCA are crucial for their protective effects in vivo [72]. To date, most studies on SERCA activation have been conducted regarding the quinoline derivative CDN1163 [73,74]. This small molecular allosteric SERCA activator balances disrupted Ca2+ homeostasis and attenuates diseases associated with ER stress, such as diabetes, metabolic disorders, neurodegenerative problems, or muscular dystrophy [75–77]. Other drug-like SERCA activators, including istaroxime and pyridone derivatives, have been reported to possess stimulatory effects on the cardiac SERCA2a isoform, making them applicable in heart failure treatment [78]. However, there is little information available on the activation of SERCA by natural compounds. Resveratrol, gingerol, ellagic acid, and luteolin belong to the most listed SERCA-targeting compounds in the literature. These compounds exhibit diverse mechanisms of action on the Ca2+ regulatory machinery, from direct interaction with SERCA, through indirect effects via inhibition of SERCA–PLB complex formation, to complex intervention in Ca2+ signaling pathways, thus contributing to various health effects summarizes up-to-date information regarding the effects of polyphenols related to SERCA activation. These compounds exhibit diverse mechanisms of action on the Ca2+ regulatory machinery, from direct interaction with SERCA, through indirect effects via inhibition of–PLB complex formation, to complex intervention in Ca2+ signaling pathways, thus contributing to various health effects. A schematic representation of the major mechanisms of polyphenols’ action with respect to intracellular Ca2+ signaling is depicted in Figure 1. 

Molecules 27 05095 g002Figure 1. A schematic representation of polyphenol-mediated effects on SERCA and related intracellular Ca2+ signaling pathways: Dietary polyphenols affect Ca2+ dynamics by targeting Ca2+ transporters and channels as well as downstream processes. Baicalein, rutin, caffeic acid, and gingerol seem to stimulate SERCA directly. On the other hand, ellagic acid, (-)-epigallocatechin-3-gallate, and tannins were described as indirect SERCA activators acting by relieving the inhibition of SERCA by PLB. Resveratrol has been shown to interact with several Ca2+-handling proteins, and to modulate Ca2+ homeostasis through intervention in Ca2+ signaling pathways. In particular, the activation of deacetylase SIRT1 has been reported as a central mechanism of resveratrol action responsible for upregulation of SERCA. The release of Ca2+ from the ER via RyRs was shown to be facilitated by baicalein, (-)-epigallocatechin-3-gallate, and rosmarinic acid. Luteolin, myricetin, and rosmarinic acid increase the overexpression of SERCA. The regulatory effects of myricetin, resveratrol, gingerol, and ellagic acid were described in relation to Ca2+-dependent channels, such as VGCCs, ORAI–STIM, and the KCa channel. Figure was created with BioRender.com.

This entry is adapted from the peer-reviewed paper 10.3390/molecules27165095

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