Article ; Online: Aberrant Adenosine Triphosphate Release and Impairment of P2Y2-Mediated Signaling in Sarcoglycanopathies.
Laboratory investigation; a journal of technical methods and pathology
2023 Volume 103, Issue 3, Page(s) 100037
Abstract: Sarcoglycanopathies, limb-girdle muscular dystrophies (LGMD) caused by genetic loss-of-function of the membrane proteins sarcoglycans (SGs), are characterized by progressive degeneration of skeletal muscle. In these disorders, muscle necrosis is ... ...
Abstract | Sarcoglycanopathies, limb-girdle muscular dystrophies (LGMD) caused by genetic loss-of-function of the membrane proteins sarcoglycans (SGs), are characterized by progressive degeneration of skeletal muscle. In these disorders, muscle necrosis is associated with immune-mediated damage, whose triggering and perpetuating molecular mechanisms are not fully elucidated yet. Extracellular adenosine triphosphate (eATP) seems to represent a crucial factor, with eATP activating purinergic receptors. Indeed, in vivo blockade of the eATP/P2X7 purinergic pathway ameliorated muscle disease progression. P2X7 inhibition improved the dystrophic process by restraining the activity of P2X7 receptors on immune cells. Whether P2X7 blockade can display a direct action on muscle cells is not known yet. In this study, we investigated eATP effects in primary cultures of myoblasts isolated from patients with LGMDR3 (α-sarcoglycanopathy) and in immortalized cells isolated from a patient with LGMDR5 (γ-sarcoglycanopathy). Our results demonstrated that, owing to a reduced ecto-ATPase activity and/or an enhanced release of ATP, patient cells are exposed to increased juxtamembrane concentrations of eATP and display a higher susceptivity to eATP signals. The purinoceptor P2Y2, which proved to be overexpressed in patient cells, was identified as a pivotal receptor responsible for the enhanced ATP-induced or UTP-induced Ca |
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MeSH term(s) | Humans ; Adenosine Triphosphate/metabolism ; Muscle, Skeletal/metabolism ; Sarcoglycanopathies/metabolism ; Signal Transduction ; Receptors, Purinergic P2Y2 |
Chemical Substances | Adenosine Triphosphate (8L70Q75FXE) ; Receptors, Purinergic P2Y2 |
Language | English |
Publishing date | 2023-01-10 |
Publishing country | United States |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 80178-1 |
ISSN | 1530-0307 ; 0023-6837 |
ISSN (online) | 1530-0307 |
ISSN | 0023-6837 |
DOI | 10.1016/j.labinv.2022.100037 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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