Inhibitors of connexin and pannexin channels as potential therapeutics

Willebrords, Joost; Maes, Michaël; Yanguas, Sara Crespo; Vinken, Mathieu

doi:10.1016/j.pharmthera.2017.07.001

Cited by 127 publications

(124 citation statements)

References 422 publications

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“…The Panx1 antagonists were used at relatively low concentrations, in order to mini mize the possible inhibition of other channels (eg connexion hemichannels). 11,30 Phenylephrine-and forskolin-induced ATP release was significantly diminished by both Panx1 inhibitors, but not by VNUT or P2X7 receptor inhibitors ( Figure 1D,E), indicating that Panx1 is the major ATP efflux pathway in ad renergically stimulated adipocytes.…”

Section: Adrenergically Stimulated Adipocytes Release Atp Through Pmentioning

confidence: 93%

Pannexin‐1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration

2019

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Aim: Extracellular ATP signalling is involved in many physiological and patho physiological processes in several tissues, including adipose tissue. Adipocytes have crucial functions in lipid and glucose metabolism and they express purinergic recep tors. However, the sources of extracellular ATP in adipose tissue are not well charac terized. In the present study, we investigated the mechanism and regulation of ATP release in white adipocytes, and evaluated the role of extracellular ATP as potential autocrine and paracrine signal. Methods: Online ATP release was monitored in C3H10T1/2 cells and freshly iso lated murine adipocytes. The ATP release mechanism and its regulation were tested in cells exposed to adrenergic agonists, insulin, glucose load and pharmacological inhibitors. Cell metabolism was monitored using Seahorse respirometry and expres sion analysis of pannexin-1 was performed on pre-and mature adipocytes. The ATP signalling was evaluated in live cell imaging (Ca 2+ , pore formation), glycerol release and its effect on macrophages was tested in co-culture and migration assays. Results: Here, we show that upon adrenergic stimulation white murine adipocytes release ATP through the pannexin-1 pore that is regulated by a cAMP-PKA-depend ent pathway. The ATP release correlates with increased cell metabolism and is sensi tive to glucose. Extracellular ATP induces Ca 2+ signalling and lipolysis in adipocytes and promotes macrophage migration. Importantly, ATP release is markedly inhibited by insulin, which operates via the activation of phosphodiesterase 3. Conclusions: Our findings reveal an insulin-pannexin-1-purinergic signalling cross talk in adipose tissue and we propose that deregulation of this signalling may contri bute to adipose tissue inflammation and type 2 diabetes. K E Y W O R D Sinflammation, obesity, P2X7 receptor, phosphodiesterase 3, purinergic signalling, type 2 diabetes This article was first published as a preprint: Tozzi M, Hansen JB, Novak I (2018) Pannexin1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration. bioRxiv. https ://doi. org/10.1101/380469 2 | RESULTS | Adrenergically stimulated adipocytes release ATP through Panx1To determine whether adipocytes are capable of releas ing ATP, we used a well-established murine cell line C3H10T1/2, as well as primary adipocytes (see below). Differentiated, mature C3H10T1/2 adipocytes were stimu lated with various agonists: α-and β-adrenergic agonists

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Section: Adrenergically Stimulated Adipocytes Release Atp Through Pmentioning

confidence: 93%

Pannexin‐1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration

2019

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“…An exception in this regard are a group of peptides that simulate amino acid modules in specific regions of connexins critical for hemichannel opening. Although promising, such peptides may cope with stability issues . Current efforts are focused on chemically stabilizing these connexin mimetic peptides in order to make them applicable for clinical use.…”

Section: Therapeutic Relevance Of Connexin and Pannexin (Hemi)channelsmentioning

confidence: 99%

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

et al. 2019

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Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin‐like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin‐based and pannexin‐based channels in noncancerous liver disease.

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“…In knock-out mice, both HCs and GJCs are deleted, as these channels are built up by the same proteins, and compensatory mechanisms are possible (Nielsen et al, 2017;Suadicani, De Pina-Benabou, Urban-Maldonado, Spray, & Scemes, 2003;Theis et al, 2003). Previously used inhibitors have poor selectivity for different Cx species, affect both HCs and GJCs, and have significant effects on other targets (e.g., pannexin HCs and voltage-gated Ca 21 channels; Carlen, 2012;Herv e & Sarrouilhe, 2005;Jin & Chen, 2011;Nielsen et al, 2017;Willebrords, Maes, Crespo Yanguas, & Vinken, 2017).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of astroglial connexin43 hemichannels with TAT‐Gap19 exerts anticonvulsant effects in rodents

Walrave

Pierre

Albertini

et al. 2018

Glia

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Accumulating evidence shows a key function for astrocytic connexin43 (Cx43) signaling in epilepsy. However, the lack of experimental distinction between Cx43 gap junction channels (GJCs) and hemichannels (HCs) has impeded the identification of the exact contribution of either channel configurations to epilepsy. We therefore investigated whether TAT-Gap19, a Cx mimetic peptide that inhibits Cx43 HCs but not the corresponding Cx43 GJCs, influences experimentally induced seizures in rodents. Dye uptake experiments in acute hippocampal slices of mice demonstrated that astroglial Cx43 HCs open in response to the chemoconvulsant pilocarpine and this was inhibited by TAT-Gap19. In vivo, pilocarpine-induced seizures as well as the accompanying increase in D-serine microdialysate levels were suppressed by Cx43 HC inhibition. Moreover, the anticonvulsant action of TAT-Gap19 was reversed by exogenous D-serine administration, suggesting that Cx43 HC inhibition protects against seizures by lowering extracellular D-serine levels. The anticonvulsive properties of Cx43 HC inhibition were further confirmed in electrical seizure mouse models, i.e. an acute 6 Hertz (Hz) model of refractory seizures and a chronic 6 Hz corneal kindling model. Collectively, these results indicate that Cx43 HCs play a role in seizures and underscore their potential as a novel and druggable target in epilepsy treatment.

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Inhibitors of connexin and pannexin channels as potential therapeutics

Cited by 127 publications

References 422 publications

Pannexin‐1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration

Pannexin‐1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

Inhibition of astroglial connexin43 hemichannels with TAT‐Gap19 exerts anticonvulsant effects in rodents

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