key: cord-0819465-n9cjn0hl authors: Dhyani, Vaibhav; Gare, Suman; Gupta, Rishikesh Kumar; Swain, Sarpras; Venkatesh, K.V.; Giri, Lopamudra title: GPCR mediated control of calcium dynamics: A systems perspective date: 2020-07-22 journal: Cell Signal DOI: 10.1016/j.cellsig.2020.109717 sha: 2ccffdacacdf9ce568f658977f56ba679f8ebaef doc_id: 819465 cord_uid: n9cjn0hl G-protein coupled receptor (GPCR) mediated calcium (Ca(2+))-signaling transduction remains crucial in designing drugs for various complex diseases including neurodegeneration, chronic heart failure as well as respiratory diseases. Although there are several reviews detailing various aspects of Ca(2+)-signaling such as the role of IP(3) receptors and Ca(2+)-induced-Ca(2+)-release, none of them provide an integrated view of the mathematical descriptions of GPCR signal transduction and investigations on dose-response curves. This article is the first study in reviewing the network structures underlying GPCR signal transduction that control downstream [Ca(c)(2+)]-oscillations. The central theme of this paper is to present the biochemical pathways, as well as molecular mechanisms underlying the GPCR-mediated Ca(2+)-dynamics in order to facilitate a better understanding of how agonist concentration is encoded by Ca(2+)-signaling. Moreover, we present the GPCR targeting drugs that are relevant for treating cardiac, respiratory, and neuro-diseases along with agonist concentration encoding of Ca(2+)-response corresponding to G(αq), G(αs,) and G(αi/o) signaling. The current paper presents the ODE formulation for various models along with the detailed schematics of signaling networks. To provide a systems perspective, we present the network motifs that can provide readers an insight into the complex and intriguing science of agonist-mediated Ca(2+)-dynamics. One of the features of this review is to pinpoint the interplay between positive and negative feedback loops that are involved in controlling intracellular [Ca(c)(2+)]-oscillations. Furthermore, we review several examples of dose-response curves obtained from [Ca(c)(2+)]-spiking for various GPCR pathways. This paper is expected to be useful for pharmacologists and computational biologists for designing clinical applications of GPCR targeting drugs through modulation of Ca(2+)-dynamics. G-protein-coupled receptors (GPCRs) are the targets of approximately 40% of all pharmaceutical drugs [1] . Activation of GPCRs is known to trigger a cascade of events that lead to the modulation of cytosolic Ca 2+ -dynamics [2] . Pharmacological compounds targeting GPCRs can be used to modulate of Ca 2+ -signaling in order to treat pro-inflammatory diseases [3, 4] . Specifically, it has been reported that cancer cells can be selectively killed and/or arrested by targeting Ca 2+ -channels [5] . The role of GPCR mediated Ca 2+ -signaling in chronic interstitial lung diseases, such as idiopathic pulmonary fibrosis and scleroderma has been reviewed by context, a more profound knowledge of the role and mechanism through which Ca 2+ is regulated by GPCRs can help in curing these diseases. Ca 2+ -dysregulation is known to be associated with many diseases in muscular and nervous systems. For example, in end-stage heart failure, the reduced level of "sarcoplasmic reticulum Ca 2+ -ATPase (SERCA)" expression leads to disturbed Ca 2+ -homeostasis [11] . Recent evidence also indicates that neuronal Ca 2+ -signaling is abnormal in many neurodegenerative disorders such as Alzheimer's, Huntington disease, and Parkinson"s disorder [12] . Within a wide variety of cells, Ca 2+ serves as an almost universal ionic messenger, delivering signals received at the cell surface to the inside of the cell. These signals are controlled by the concentration of the modulating agonists and encoded in the complex spatiotemporal behavior of cytosolic Ca 2+ -concentration ([ ]), ranging from stochastic spiking to regular oscillations, and more complex waveforms [13] . Ca 2+ -signals regulate the intracellular processes operating over a wide time range, from neurotransmission in microseconds to gene transcription at a scale of minutes to hours [14] . Cells can quickly raise or reduce the [ ] through tight regulation mediated through GPCRs, Ca 2+ -stores, channels, pumps, and exchangers. GPCR mediated [ ]-oscillations are known to control a wide range of cellular functions amid and including cell division to apoptosis [15, 16] . While in excitable cells, these functions include muscle contraction [17] , neurotransmitter release [18] , Ca 2+ regulates transcription [19] and cell cycle progression [20] in the non-excitable cells. For pancreatic β-cells, Ca 2+ -dynamics control the changes in insulin secretion [21] . Vital cellular functions like fertilization, development, differentiation, adhesion, growth, secretion, platelet activation, gene expression, and memory are also linked to Ca 2+ -signaling regulated by GPCRs [22, 23] . Ca 2+ mediates these functions by [ ]-sensing effectors that translate Ca 2+ -signals with varying spatiotemporal dynamics into specific cellular responses [24] . In this scenario, the recent scientific efforts are focusing on drug screening and testing based on the quantification of Ca 2+ -signatures over conventional biochemical assays [13, 25] . Several review papers have been published in the last three decades on the function and structure of GPCR targeting drugs as well as bimolecular details of Ca 2+ -signaling [26] [27] [28] . Many of them focus on providing a quantitative description of Ca 2+ -toolbox and a thorough understanding of J o u r n a l P r e -p r o o f Journal Pre-proof non-linear coupled systems [27] [28] [29] [30] . One of these review articles characterizes the biophysical and biochemical mechanisms of Ca 2+ -signaling in astrocytes [27] . However, the review does not elucidate the interplay between positive and negative feedback loops yielding oscillations and how GPCR targeting agonists may encode various levels of frequencies. Another review emphasizes the key features of modeling of Ca 2+ -induced-Ca 2+ -release (CICR) through inositol trisphosphate (IP 3 )-receptors (IP 3 R) and ryanodine receptors (RyR) and how local Ca 2+ -release affects global oscillations [30] . The role of Ca 2+ -entry through store-operated channels in controlling Ca 2+ -signaling is emphasized in Dupont et al. [31] . However, none of these reviews GPCRs are the heptahelical receptors on the plasma membrane that are coupled to guanine nucleotide-binding proteins (G-proteins) within the cell. The binding of the agonist to the extracellular domain of the GPCR activates the receptor and leads to a conformational change on the intracellular side of the membrane. Subsequently, the G-protein (that has three subunits, α, β, and γ) is activated in response to this conformational change. Based on the type of G-protein"s αsubunit activated, the GPCRs can be classified into three major types, G αq , G αs, and G αi/o coupled receptors, where each type has its own signal transduction mechanism ( Figure 1) . Various examples of GPCRs that are known to regulate Ca 2+ -signaling through G αq , G αs , or G αi/o pathways are presented in Table 1 . Representative FDA approved GPCR targeting drugs used to treat some of the respiratory, cardiovascular, and nervous system diseases has also been shown in to altered cellular activity [29, 42] . As per several mechanistic models, [ ] provides positive feedback on IP 3 either directly [43, 44] or indirectly via stimulation of PLC [45] (Figure 1(a) ). Paroxetine (G αq ) is known to induce apoptosis through an increase in intracellular Ca 2+ and the generation of reactive oxygen species (ROS) [46] . ryanodine receptor (RyRs), and myosin binding protein C. It has been shown that the activation of β-adrenergic stimulation may enhance SR Ca 2+ -release through phosphorylation of LCCs, or due to phosphorylation of LCCs and RyRs [47, 48] . In the G αi/o pathway, subunit of G-protein is known to inhibit the cAMP production as well as voltage-gated Ca 2+ -channels (VGCCs). In contrast to the G αq pathway, the PLC pathway is activated here by subunit (Figure 1(c) ). Melatonin (G αi/o ) is known to fine-tune intracellular Ca 2+ and eliminate myocardial damage through IP 3 R/mitochondrial uniporter pathway [49] . To date, the foremost modeling approach to investigate the [ ]-oscillations in cells is based on numerical solutions of a system of differential equations (Table 2 ) [29] . Here, we describe two of these models to explain how computational modeling can be used to yield agonist- Their model was compared with experimental data obtained from hepatocytes stimulated with phenylephrine (G αq ) and ATP, but no parameter estimation was performed. [ ] To depict the differential translocation rates, they assumed a fast gamma subunit and slow gamma subunit as where and are the rate constants of fast and slow subunits. Equation (5) and (6) represent the active fast and slow gamma subunits at the plasma membrane and equation (7) and (8) (3) and (4). The parameter in equation (5) and (6) The detailed investigation of the models depicting receptor-mediated Ca 2+ -dynamics shows that the circuits include four types of feedback including positive feedback of agonist on PLC [54, 59, 60] , Ca 2+ -feedback on the IP 3 R (Ca 2+ activation and inhibition of the IP 3 R) [61] , positive feedback of Ca 2+ on PLC [62] , and negative feedback of Ca 2+ on IP 3 by activation of IP 3 -kinase [63] . Table 2 resolution. This makes Ca 2+ -flux assay as a novel tool in GPCR drug discovery [35] . Specifically, Ca 2+ -imaging offers a platform for high-content and optimal drug-dose screening. It has been shown that confocal imaging-based assays can be used for measurement of response at a higher spatial resolution that can be further used for classification of responses using k-means clustering and ranking of drugs [52] . Since there are a significant number of potential candidate drugs for the treatment of cardiac diseases, neuro-diseases and respiratory complications ( Figure 2 ), Ca 2+ -imaging and systems pharmacology based platforms can be used for testing various drugs and drug-drug interactions. Moreover, Ca 2+ -imaging offers a phenotypic drug discovery paradigm [71] . Additionally, fluorescence resonance energy transfer (FRET) based Ca 2+ -imaging has been shown as an attractive alternative for the identification of novel Alzheimer's disease therapeutics [72] . spikes obtained through stimulation of serotonin 1A receptor (G αq coupled) in CHO cells ( Figure 6 (a)). In another study [50] , the dose-response curve with respect to the amplitude of acetylcholine (Ach, G αq ) mediated [ ]-oscillation has been reported ( Figure 6(b) ). An example of dose-response of 2-chloro-N6-cyclopentyladenosine targeting Adenosine-A1 receptor (G αi/o coupled) in terms of AUC has also been shown in Figure 6 (c). The construction of such a dose-response curve and analysis of [ ]-oscillations can provide valuable insights into drug potential, which can further aid in the faster in-vitro screening of drugs [52, 74] . Most of the existing studies that combine experimental, as well as computational investigations on dose responses, are able to capture a qualitative similarity between the predicted and experimental responses. However, cell-specific modeling of Ca 2+ -dynamics along with parameter estimation using an evolutionary algorithm can be crucial for the prediction of drugdose response [25] . Another limitation of the models referred here is that they are based on the "well-stirred-reactor" assumption where all components of the signaling cascade are uniformly distributed in the cytoplasm. A state-of-art approach is to model the system as a reaction-diffusion process using partial differential equations and incorporation of stochastic parameters that are less assumptive and accounts for the inherent variability in receptor states at different time points [77, 78] . However, such an approach is computationally expensive. In the future, such models have the potential to generate stochastic cellular response and cell-to-cell variability and validate the doseresponse curves at tissue levels. It has been noticed that a large amount of information is available on GPCR targeting agonists that are central in treating cardiac, respiratory and neuro-diseases, and activate G αq , G αs, and G αi/o pathways to regulate the Ca 2+ -dynamics (Table 1 and Figure 2 Tables Table 1. Examples of GPCRs along with various agonists and antagonists involved in regulating Ca 2+ -dynamics [33] [34] [35] [36] [37] [38] [39] [40] [41] . 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