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

Abstract

Immune-mediated inflammatory diseases (IMIDs) encompass a wide range of seemingly unrelated conditions, such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, asthma, chronic obstructive pulmonary disease, and systemic lupus erythematosus. Despite differing etiologies, these diseases share common inflammatory pathways, which lead to damage in primary target organs and frequently to a plethora of systemic effects as well. The purinergic signaling complex comprising extracellular nucleotides and nucleosides and their receptors, the P2 and P1 purinergic receptors, respectively, as well as catabolic enzymes and nucleoside transporters is a major regulatory system in the body. The purinergic signaling complex can regulate the development and course of IMIDs. Here we provide a comprehensive review on the role of purinergic signaling in controlling immunity, inflammation, and organ function in IMIDs. In addition, we discuss the possible therapeutic applications of drugs acting on purinergic pathways, which have been entering clinical development, to manage patients suffering from IMIDs.

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

“…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].…”

Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium

“…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].…”

Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

“…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).…”

“…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.…”