Table 2.

A summary table of the 22 research papers analysed following a systematic search protocol for papers including “sigma-1 receptor” and “cardiac”. For each paper, the methods, materials, results, limitations and further work suggested are summarised.

Author(s)	Material used	Techniques used	Results and discussion	Limitations suggested by authors	Further work suggested by authors
Gao et al., 2018 [59]	Adult male Sprague-Dawley rats (220-250g)	Intraperitoneal injection of PRE-084 or saline, LAD ligation to induce myocardial ischaemia, followed by reperfusion, haemodynamic measurements, TUNEL assay, Western blotting	Treatment with Sigma-1R agonist PRE-084 increased recovery of haemodynamic function and reduced apoptosis, after myocardial I/R injury; cardioprotective mechanism likely via Akt-eNOS pathway and decreasing apoptosis via changing expression of apoptotic-related proteins	Animals pre-treated with PRE-084 (vs in clinical setting, they will be treated after MI). Previous studies showed PRE-084 protects the heart by stimulating Sigma-1R in brain	Sigma-1R interacts with ion channels, including Ca2+, K+, Na+, Cl− channels, potential mechanisms to be elicited; PRE-084 to treat myocardial I/R injuries
Liu et al., 2017 [61]	Homozygous Sigma-1R KO mice, HEK293 cells	CRISPR/Cas9, Western blotting, immunohistochemistry, electrophysiology, electroretinogram, intravitreal injection	Sigma-1R selective ligands potently inhibited Kv2.1 currents, but in a sig-R independent manner, as the ligands exerted similar effect in WT and Sigma-1R KO cells		Therapeutic opportunities – conciliating drug effects on Sig-Rs and the Kv2.1 channel
Alam et al., 2017 [49]	Primary neonatal rat ventricular cardiomyocytes (NRCs) from 1 to 2-day old Sprague-Dawley rat pups	Adenovirus-mediated Sigma-1R overexpression, siRNA-mediated sigma-1R knockdown, tunicamycin, immunocytochemistry, Western blotting, immunoprecipitation, LDH release assay	Sigma-1R found to mediate the IRE1a-XBP1 response to ER stress in cardiomyocytes. Overexpression of sigma-1R led to increase in IRE1a phosphorylation, increase XBP1 expression and nuclear localisation, decrease in CHOP expression		Study the direct role of Sigma-1R in specific ER-response pathways; study pathway-specific gene activation programmes in vivo in various pathological conditions
Bao et al., 2017 [62]	Neonatal rat cardiomyocytes, adult male Sprague-Dawley rats	Bioinformatic analysis, TAC, echocardiography, histological staining, transfection, dual-luciferase reporter assay, immunofluorescence, qRT-PCR, Western blotting	miR-297 negatively and directly regulates Sigma-1R expression. Increased miR-297 observed in hypertrophic models, correlated with decreasing Sigma-1R levels. miR-297 promotes CM hypertrophy by inhibiting the expression of Sigma-1R and activation of ER stress signalling, specifically XBP1 and ATF4 pathways	Precise mechanism by which Sigma-1R induces splicing of Xbp1 by IRE1a not explored; activation of ATF4 not explored in the study	Sigma-1R and inhibition of miR-297 as a potential treatment for cardiac hypertrophy
Shinoda et al., 2016 [27]	Neonatal rat ventricular cardiomyocytes from Wistar rats, ICR mice	TAC-induced hypertrophy, ANGII-induced hypertrophy mitochondrial staining, immunocytochemistry, Western blot, qRT-PCR, echocardiography, morphological analysis, histological analysis, ATP content assay, ratiometric dyes for intracellular and mitochondrial Ca2+ measurement, TUNEL staining for apoptosis	Treating cardiomyocytes and mice with haloperidol altered the mitochondrial calcium transport via inhibiting Sigma-1R expression. This leads to impaired mitochondrial ATP production and hence adverse cardiac remodelling and impairment of cardiac function. ATP supplementation with sodium pyruvate rescues ATP levels in haloperidol-treated TAC mice and recovers cardiac function.		Suggests supplementing schizophrenic patients treated with haloperidol with ATP supplementation (eg sodium pyruvate) may prevent adverse effects on cardiac function
Stracina et al., 2015 [63]	Guinea pigs	Haloperidol administration, qRT-PCR of Sigma-1R and IP3R expression, immunohistochemical staining, Langendorff-perfusion, ECG (to study QT interval and detect arrhythmia)	Increased expression Sigma-1R in atrial cardiomyocytes in guinea pigs exposed to haloperidol. Increased signalling via Sigma-1R and IP3 receptor occurred in haloperidol-treated groups. Chronic haloperidol administration significantly decreased heart rate over time. Exposure to haloperidol increased the QT interval, suggested to be related to IKr activity. Haloperidol in guinea pig hearts increases gene expression of Sigma-1R and IP3Rs. This may lead to altered calcium handling, such as affecting the availability of calcium ions in cardiomyocytes which subsequently lowers the arrhythmogenic threshold.		Further studies need to understand how acute and chronic haloperidol treatment affects the IKr current, calcium availability and if its influences the co-localisation of Sigma-1R and IP3Rs.
Balasuriya et al., 2014 [51]	tsA 201 cells (HEK-293 subclone)	Cell culture, transient transfection with DNA encoding sigma-FLAG, immunofluorescence, in situ proximity ligation assay, AFM imaging of isolated proteins, extracellular HTRF	Sigma-1R was shown to promote hERG protein expression within the plasma membrane. Sigma-1R ligands showed no effect on hERG expression. Sigma-1R likely binds to an immature hERG protein, seems to occur in the ER and its expression is enhanced with Sigma-1R is co-expressed, albeit this seems to have no effect on its activation within the cell. Sigma-1R seems to reduce expression of mature hERG in cells.		Studies into the interactions with sigma-1R to understand its mechanisms of action with selective ligands and cholesterol. With a suggestion that hERG is involved in cardiac arrhythmias, a clearer understanding of this interaction may provide potential therapeutic approaches.
Tagashira et al., 2014 [28]	Adult male ICR mice, neonatal rat ventricular cardiomyocytes	TAC, ANGII-treatment to induce hypertrophy, RNAi by siRNA, morphological analysis of cells, mitochondrial staining, immunocytochemistry, Western blotting, ratiometric measurement of intracellular and mitochondrial Ca2+ (by FURA2 and pericam), measurement of ATP content in vitro and in vivo	Imbalance of Sigma-1R and IP3R2 expression was found in hypertrophic models, leading to dysregulation of IP3R2 function due to dissociation from Sigma-1R. Fluvoxamine (Sigma-1R agonist) leads to upregulation of Sigma-1R, thereby (1) stabilising the Sigma-1R/ IP3R2 complex on MAMs, allowing for Ca2+ transport into mitochondria and hence ATP production, as well as (2) suppressing intracellular Ca2+ overload by inhibiting IP3R2 and RyR-mediated Ca2+ release from SR.		Further studies to define the regulatory role of RyR-mediated Ca2+ release into cytosol by Sigma-1R, to determine potential interaction between Sigma-1R and TRPCs in CMs, explore mechanisms underlying Sigma-1R mediated inhibition of fission or enhancement of mitochondrial elongation
Tagashira et al., 2013 [29]	Female adult Wistar rats, primary culture of neonatal rat ventricular cardiomyocytes	Bilateral ovariectomy, abdominal aortic banding, heart weight measurement, qRT-PCR, histological techniques (Masson’s trichome staining), haemodynamic measurements, immunohistochemistry, ANGII treatment to induce CM hypertrophy, cross-linking and immunoprecipitation, Western blot, ATP content measurement, intracellular Ca2+ measurement using FURA2	Pentazocine, a Sigma-1R agonist, prevented downregulation of Sigma-1R in hypertrophy. Sigma-1R stimulation with pentazocine was found to be cardioprotective in inhibiting cardiac hypertrophy and dysfunction, by restoring IP3R-mediated Ca2+ entry into mitochondria and hence ATP production, as well as inhibiting RyR-mediated Ca2+ leakage into cytoplasm.	Did not define the association regions between Sigma-1R and RyR2 (- to be done in future studies)	Studies should identify the mechanism where RyR2-mediated calcium release by sigma-1R is regulated and the associated molecular regions between these two receptors. Further studies required to identify mechanisms underlying regulation of RyR2-mediated Ca2+ release into cytosol by Sigma-1R.
Amer et al., 2013 [64]	Endothelial cells (from human saphenous vein) and HEK-293 cells	Application of Sigma-1R agonist and antagonist, siRNA to decrease Sigma-1R expression, fluorescence microscopy, measurement of intracellular Ca2+, whole-cell patch clamp	Multiple Sigma-1R agonists and antagonists applied with different results. Some ligands were inhibitory, some were stimulatory while some did not exert effects on transient calcium channels. Specifically, BD1047/BD1063 and 4-IBP are inhibitors of receptor/chemically-activated calcium entry channels. They seem to act directly and independently of Sigma-1R.		Sigma-1R ligands exert pharmacologically effect rather independently of Sigma-1R: important information for developing therapeutic drugs
Delaunois, et al., 2012 [65]	Conscious tethered Sprague-Dawley rats with intra-arterial catheter and tethers	Repeated handling and dosing with sigma-1R agonists and antagonists, HR, SBP, DBP, MAP recorded	Endogenous Sigma-1R activation may contribute to stress-induced tachycardia. 3 out of 4 agonists decrease this phenomenon; antagonists have no effect. Neither had effect on HR during and after the dosing procedure. Sigma-1Rs are involved in the stress response but not in its initiation. Findings suggest that mechanisms underlying HR regulation involving Sigma-1Rs differ according to different conditions.	Did not evaluate the anxiolytic properties of the Sigma-1R ligands	Further studies should look at the possible link between the baroreflex function of the heart and sigma-1R activation. Studies on cardiac contractility in vivo should be assessed to understand the effects of drugs acting on Sigma-1Rs.
Tagashira et al., 2011 [24]	Female Wistar rats	Bilateral ovariectomy, TAC (abdominal aorta) in rats, oral DHEA and subcutaneous E2 administration, haemodynamic measurements, Western blot, qRT-PCR, heart weight measurement	PO-induced hypertrophy reduced Sigma-1R expression; DHEA and E2 cardioprotective, act via increasing p-Akt, eNOS and p-eNOS. DHEA increased Sigma-1R (mRNA and protein), E2 did not. DHEA likely act via Sigma-1R, while E2 does not	DHEA(S) not found normally circulating in mice or rats. DHEA administered in the experiment is of a higher concentration that normal human circulating levels. DHEA may have acted via other Sigma-1R-independent mechanisms, such as PPARα.	To determine the localisation of Sigma-1R in cardiomyocytes after DHEA treatment (to elicit if the mechanism of action is via stabilising IP3R); DHEA as potential hormonal therapy candidate as compared to estrogens (E2)
Crottès et al., 2011 [66]	K562 and HEK 293 cell lines, Xenopus laevis	cDNA preparation, patch clamp, double electrode voltage clamp, adhesion experiments, Western blot (hERG, Sigma-1R), shRNA lentiviral transduction, co-immunoprecipitation, flow cytometry, transfection of HEK 293 cells with hERG1 and Sigma-1R, qRT-PCR, pulse chase	In HEK cells expressing hERG and sig1R, both proteins co-immunoprecipitate, indicating physical association. Sigma-1R expression enhances hERG protein maturation and stability. Sigma-1R controls hERG expression through the regulation of subunit trafficking activity		Sigma-1R to be considered as a new pharmacological target to reduce membrane signalling complexes activity with implications in cancer treatment
Novakova et al., 2010 [67]	Cardiomyocytes	Chronic administration of haloperidol, Langendorff-perfusion, ECG, qRT-PCR, Western blot	Haloperidol treatment affects expression of IP3R1 and 2 in atria but not in ventricles. Increase in IP3R may be involved in arrhythmia, but increase is likely due to upregulation at neuronal level rather than cardiomyocyte level	Did not prove the direct link between QTc interval changes and arrhythmias	Further verification needed regarding the theory that increase in IP3R gene expression in neuronal cells rather than cardiomyocytes contribute to arrhythmogenesis
Johannessen et al., 2010 [52]	HEK293 cells	siRNA to knockdown Sigma-1R, electrophysiology, drug application of both agonists and antagonists, Sig-R competitive binding assays, photoaffinity labelling	Progesterone binds to Sigma-1R and Sig-2Rs, and blocks photolabeling of these 2 receptors in HEK293 cells; Progesterone inhibits the channel modulation effects of Sig-R ligands. Progesterone binding to Sig-Rs block Sig-R-mediated modulation of a voltage-gated ion channel		Since Sig-Rs modulate a wide range of ion channels, necessary to test other channels for Sig-R/progesterone interactions in the future. Furthermore, other steroids that bind to Sig-R, such as testosterone, DHEA and cholesterol should also be tested
Tagashira et al., 2010 [23]	Adult male ICR mice and murine neonatal ventricular myocytes	TAC (aortic arch), oral fluvoxamine and paroxetine maleate, heart weight measurement, echocardiography, Western blot, morphological analysis, si-RNA transfection, Western blot	Fluvoxamine treatment protects against TAC-induced cardiac hypertrophy and ANG-II induced cardiomyocyte hypertrophy, via increased expression of sigma-1R, likely mediated by the Akt-eNOS signalling pathway		Mechanism in which fluvoxamine treatment causes upregulation/ stabilisation of Sigma-1R is to be elucidated; to understand how chronic fluvoxamine treatment affects Sigma-1R; potential for development of a new class of antihypertrophic drugs
Bhuiyan et al., 2010 [18]	Adult male and female Wistar rats	Bilateral ovariectomy in female rats, abdominal aortic banding, oral fluvoxamine and NE-100 administration, haemodynamic measurements, Western blot, heart weight measurement, immunohistochemistry	Sigma-1R expression in the heart can attenuate PO-induced hypertrophy in ovariectomised rats; Sigma-1R agonist fluvoxamine treatment protects against PO-induced hypertrophy via upregulating Sigma-1R and stimulating Sigma-1R mediated Akt-eNOS signalling		To understand how chronic fluvoxamine treatment affects Sigma-1R; potential for development of a new class of antihypertrophic drugs
Bhuiyan and Fukunaga, 2009 [25]	Female Wistar rats	Bilateral ovariectomy, abdominal aortic banding in rats, oral DHEA administration, haemodynamic measurements, Western blot, heart weight measurement	Sigma-1R expression in the heart can attenuate PO-induced hypertrophy in ovariectomised rats; Sigma-1R agonist DHEA treatment protects against PO-induced hypertrophy via upregulating Sigma-1R amd stimulating Sigma-1R mediated Akt-eNOS signalling	DHEA(S) not found normally circulating in mice or rats; administered DHEA in the experiment is also higher concentration than normal human circulating levels	Potential for development of a new class of antihypertrophic drugs
Johannessen et al., 2009 [53]	Neonatal mouse cardiac myocyte	siRNA to knockdown Sigma-1R, electrophysiology, drug application of both agonists and antagonists, photoaffinity labelling	Sigma-1R ligands (SKF-10047, pentazocine, haloperidol and ditoylguanidine) reversibly inhibited Nav1.5 in HEK293 and COS-7 cells, also inhibited Na+ current in neonatal mouse cardiac myocytes; Sig-Rs inhibits Nav1.5 channels and thus the INa, likely inhibit contractility and rhythmicity		Other research showed Sigma-1R to inhibit inwardly rectifying K+ and hERG K+ channels, which will stimulate contractility and rhythmicity, while inhibiting Na+ channels have the opposite effect – investigate how the opposing effects are resolved. Potential future applications for anti-arrhythmics
Fontanilla et al., 2009 [68]	HEK293 cells	Competitive binding assays, electrophysiology, drug application, photoaffinity labelling	DMT bound to sigma-1R, inhibited Na+ channels in native cardiac myocytes and heterologous cells that express sigma-1Rs. DMT induced hypermobility in WT mice but not in sigma-1R knock-down mice, suggesting that DMT is an endogenous agonist for Sigma-1R
Zhang and Cuevas, 2005 [58]	Neonatal rat intracardiac ganglia	Electrophysiological techniques (whole-cell patch-clamp)	Stimulation of sigma-1Rs inhibit multiple voltage-gated K+ channel subtypes via direct coupling (delayed outwardly rectifying potassium channels, large conductance Ca2+-sensitive K+ channels, and the M-channel) and depresses excitability in intracardiac neurons	Inhibition of voltage-gated K+ channels alone cannot explain the complete block of action potential firing at high concentrations of sig ligands – sig-Rs likely to affect other channel types that affect AP firing (e.g. voltage-gated Na+ channels)	Sig-R modulation of other mechanisms of Ca2+ entry or homeostasis must be examined to confirm a direct effect of sigma-1R on Ik(Ca)
Zhang and Cuevas, 2002 [57]	Neonatal rat intracardiac ganglia	RT-PCR and gel electrophoresis of total RNA extracts and single-cell RNA extracts, electrophysiological studies (voltage-clamp using perforated-patch configuration of whole cell patch-clamp recording technique, electrophysiological methods), bath application of sigma-1R agonists	Sigma-1Rs found to be expressed in neonatal rat intracardiac neurons. Application of Sig-R agonists inhibited all Ca2+ channel subtypes in the neurons. Sig-R activation depressed the peak Ca2+ channel current, increased the rate of Ca2+ channel inactivation, and shifted the voltage-dependence of steady-state inactivation and activation towards more negative potentials. However, modulation of Ca2+ channel activity is likely only via the Sig-2R		Function of Sigma-1R in autonomic neurons remains to be elucidated.