Regulation of pannexin and connexin channels and their functional role in skeletal muscles

Abstract

Myogenic precursor cells express connexins (Cx) and pannexins (Panx), proteins that form different membrane channels involved in cell-cell communication. Cx channels connect either the cytoplasm of adjacent cells, called gap junction channels (GJC), or link the cytoplasm with the extracellular space, termed hemichannels (HC), while Panx channels only support the latter. In myoblasts, Panx1 HCs play a critical role in myogenic differentiation, and Cx GJCs and possibly Cx HCs coordinate metabolic responses during later steps of myogenesis. After innervation, myofibers do not express Cxs, but still express Panx1. In myotubes and innervated myofibers, Panx1 HCs allow release of adenosine triphosphate and thus they might be involved in skeletal muscle plasticity. In addition, Panx1 HCs present in adult myofibers mediate adenosine triphosphate release and glucose uptake required for potentiation of muscle contraction. Under pathological conditions, such as upon denervation and spinal cord injury, levels of Panx1 are upregulated. However, Panx1(-/-) mice show similar degree of atrophy as denervated wild-type muscles. Skeletal muscles also express Cx HCs in the sarcolemma after denervation or spinal cord injury, plus other non-selective membrane channels, including purinergic P2X7 receptors and transient receptor potential type V2 channels. The absence of Cx43 and Cx45 is sufficient to drastically reduce denervation atrophy. Moreover, inflammatory cytokines also induce the expression of Cxs in myofibers, suggesting the expression of these Cxs as a common factor for myofiber degeneration under diverse pathological conditions. Inhibitors of skeletal muscle Cx HCs could be promising tools to prevent muscle wasting induced by conditions associated with synaptic dysfunction and inflammation.

iPSC-derived functional human neuromuscular junctions model the pathophysiology of neuromuscular diseases

“…Optogenetic neuronal excitation controls muscular contraction in mature hNMJ culture. In adult NMJs in vivo, spontaneous muscle contractions usually do not occur because of the loss of spontaneous neuronal excitation and gap junction-dependent electrical connections in myotubes (31). Although in vitro tracking of hNMJ development is an advantage of our system, it also causes the spontaneous halting of muscular contraction and limits the period of functional evaluation.…”

Manipulation of Panx1 Activity Increases the Engraftment of Transplanted Lacrimal Gland Epithelial Progenitor Cells

“… 6 , 15 , 75 – 77 In addition the role of Panx1 in acute inflammation has been reported. 78 , 79 In current study, we demonstrated that Panx1 is highly expressed in the epithelial components of the mouse and human LGs and that progenitor cell engraftment into injured LGs was significantly improved by the blocking of Panx1 function. These findings suggest that stem/progenitor cells function more efficiently when inflammation is downregulated and the regeneration process is induced.…”

“… 14 Moreover, these findings support a consensus view that Panx1 is an important mediator of inflammation. 78 , 79 Our model suggests that transplantation of progenitor cells at high level of inflammation results in their poor survival ( Fig. 6 A), whereas blocking Panx1 in the LG decreases the level of inflammation and promotes progenitor cell survival/function within the LG ( Fig.…”

Astrocyte Pannexin 1 Suppresses LPS-Induced Inflammatory Responses to Protect Neuronal SH-SY5Y Cells

“…Thus, to elucidate the role of astrocyte Panx 1 in PD, subregional heterogeneity needs to be considered in addition to the secreted molecules. Of note, given with the ubiquitous expression of Panx 1, the role of Panx 1-mediated neuroinflammation could be implicated in many of other disease ( Saez et al, 2015 ; Scemes et al, 2019 ; Spray and Hanani, 2019 ; Sanchez Arias et al, 2020 ) and therefore could represent a potential therapeutic target.…”