The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

Antonioli, Luca; Blandizzi, Corrado; Pacher, Pál; Haskó, György

doi:10.1124/pr.117.014878

Cited by 118 publications

(110 citation statements)

References 403 publications

(454 reference statements)

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“…For example, agonists of P2Y2 receptors activate human cardiac fibroblast proliferation and migration [104]. Among the eight purinergic P2Y receptors (P2YRs) [101,105], five Gq-coupled receptors (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11) can be detected by RT-PCR, immunostaining, and a functional assay that measures inositol phosphate (IP) production in rat myofibroblasts [106].…”

Section: Signaling Pathways Mediating Ca 2+ Release In Cardiac Fibrobmentioning

confidence: 99%

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Feng

Armillei

et al. 2019

JCDD

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Cardiac fibrosis is the excessive deposition of extracellular matrix proteins by cardiac fibroblasts and myofibroblasts, and is a hallmark feature of most heart diseases, including arrhythmia, hypertrophy, and heart failure. This maladaptive process occurs in response to a variety of stimuli, including myocardial injury, inflammation, and mechanical overload. There are multiple signaling pathways and various cell types that influence the fibrogenesis cascade. Fibroblasts and myofibroblasts are central effectors. Although it is clear that Ca2+ signaling plays a vital role in this pathological process, what contributes to Ca2+ signaling in fibroblasts and myofibroblasts is still not wholly understood, chiefly because of the large and diverse number of receptors, transporters, and ion channels that influence intracellular Ca2+ signaling. Intracellular Ca2+ signals are generated by Ca2+ release from intracellular Ca2+ stores and by Ca2+ entry through a multitude of Ca2+-permeable ion channels in the plasma membrane. Over the past decade, the transient receptor potential (TRP) channels have emerged as one of the most important families of ion channels mediating Ca2+ signaling in cardiac fibroblasts. TRP channels are a superfamily of non-voltage-gated, Ca2+-permeable non-selective cation channels. Their ability to respond to various stimulating cues makes TRP channels effective sensors of the many different pathophysiological events that stimulate cardiac fibrogenesis. This review focuses on the mechanisms of Ca2+ signaling in fibroblast differentiation and fibrosis-associated heart diseases and will highlight recent advances in the understanding of the roles that TRP and other Ca2+-permeable channels play in cardiac fibrosis.

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Section: Signaling Pathways Mediating Ca 2+ Release In Cardiac Fibrobmentioning

confidence: 99%

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Feng

Armillei

et al. 2019

JCDD

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“…A list with some toxins which bind to VGCC channels can be found in [140]. For other pharmacologically active substances that modulate calcium homeostasis, please refer to reviews on TRP channels [141,142], purinergic receptors [143], IP3R and RyR [144].…”

Section: Other Calcium Channel Blockers Modulators Affecting the Cnsmentioning

confidence: 99%

Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium

Enders

Heider

Ludwig

et al. 2020

IJMS

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Calcium ions are vital for maintaining the physiological and biochemical processes inside cells. The central nervous system (CNS) is particularly dependent on calcium homeostasis and its dysregulation has been associated with several neurodegenerative disorders including Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD), as well as with multiple sclerosis (MS). Hence, the modulation of calcium influx into the cells and the targeting of calcium-mediated signaling pathways may present a promising therapeutic approach for these diseases. This review provides an overview on calcium channels in neurons and glial cells. Special emphasis is put on MS, a chronic autoimmune disease of the CNS. While the initial relapsing-remitting stage of MS can be treated effectively with immune modulatory and immunosuppressive drugs, the subsequent progressive stage has remained largely untreatable. Here we summarize several approaches that have been and are currently being tested for their neuroprotective capacities in MS and we discuss which role calcium could play in this regard.

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“…Molecules that subserve purinergic signaling, that is, adenosine, inosine, ATP, and various other adenine and uracil nucleotides, are ubiquitously present in living tissues, and their receptors are present in some combination in nearly every cell [13] . Purinergic receptors include both GPCRs (ARs and P2Y receptors (P2YRs) for purine and pyrimidine nucleotides) and ligand‐gated P2X receptors (Figure 1).…”

Section: Purinergic Gpcrsmentioning

confidence: 99%

“…Purinergic receptors include both GPCRs (ARs and P2Y receptors (P2YRs) for purine and pyrimidine nucleotides) and ligand‐gated P2X receptors (Figure 1). [13] A temporal sequence of signaling, which is involved in physiology and pathology, regulates the innate immune system and many other processes in responding to challenges. Multiple enzymes and transporters in the purinergic system, such as adenosine kinase (ADK, removes intracellular adenosine), adenosine deaminase (ADA, converts adenosine into inosine), CD39/CD39L1 (nucleoside triphosphate diphosphohydrolases 1/2, NTPDase1/2, form extracellular AMP) and CD73 (ecto‐5′‐nucleotidase, forms extracellular adenosine), and equilibrative nucleoside transporter 1 (ENT1 in the SLC29 family, effecting communication between intra‐ and extracellular adenosine pools), control the endogenous agonist levels.…”

Section: Purinergic Gpcrsmentioning

confidence: 99%

Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

Salmaso

2020

ChemMedChem

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The purinergic signaling system includes membrane‐bound receptors for extracellular purines and pyrimidines, and enzymes/transporters that regulate receptor activation by endogenous agonists. Receptors include: adenosine (A1, A2A, A2B, and A3) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) receptors (all GPCRs), as well as P2X receptors (ion channels). Receptor activation, especially accompanying physiological stress or damage, creates a temporal sequence of signaling to counteract this stress and either mobilize (P2Rs) or suppress (ARs) immune responses. Thus, modulation of this large signaling family has broad potential for treating chronic diseases. Experimentally determined structures represent each of the three receptor families. We focus on selective purinergic agonists (A1, A3), antagonists (A3, P2Y14), and allosteric modulators (P2Y1, A3). Examples of applying structure‐based design, including the rational modification of known ligands, are presented for antithrombotic P2Y1R antagonists and anti‐inflammatory P2Y14R antagonists and A3AR agonists. A3AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain.

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The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

Cited by 118 publications

References 403 publications

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium

Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

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