Pannexin channels in ATP release and beyond: An unexpected rendezvous at the endoplasmic reticulum

D’hondt, Catheleyne; Ponsaerts, Raf; Smedt, Humbert De; Vinken, Mathieu; Vuyst, Elke De; Bock, Marijke De; Wang, Nan; Rogiers, Vera; Leybaert, Luc; Himpens, Bernard; Bultynck, Geert

doi:10.1016/j.cellsig.2010.07.018

Cited by 93 publications

(88 citation statements)

References 187 publications

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“…The control of [Ca 2ϩ ] ER requires a tight handling of these mechanisms, because an increase in [Ca 2ϩ ] ER renders cells hypersensitive toward agonist-induced Ca 2ϩ signaling, whereas a decrease in [Ca 2ϩ ] ER may provoke ER stress and the activation of the unfolded protein response (3,4). The passive Ca 2ϩ leak has been one of the most enigmatic paradigms in Ca 2ϩ signaling, given the poor understanding of the molecular mechanisms and candidates responsible for the passive Ca 2ϩ leak (5). Recent work from the laboratories of Reed and Chae (6,7) demonstrated that Bax inhibitor-1 (BI-1) affects passive Ca 2ϩ leak from the ER.…”

Section: The Endoplasmic Reticulum (Er)mentioning

confidence: 99%

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The C Terminus of Bax Inhibitor-1 Forms a Ca2+-permeable Channel Pore

Bultynck

Kiviluoto

Henke

et al. 2012

Journal of Biological Chemistry

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102

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Background: Evolutionary conserved Bax inhibitor-1 (BI-1) protects against ER stress-mediated apoptosis. Results: We identified a Ca 2ϩ -permeable channel pore in the C terminus of BI-1. Critical pore properties are an ␣-helical structure and two aspartate residues conserved among animals, but not among plants and yeast. Conclusion: C-terminal domain of BI-1 harbors a Ca 2ϩ -permeable channel pore. Significance: BI-1 has Ca 2ϩ channel properties likely relevant for its function in ER stress and apoptosis. Bax inhibitor-1 (BI-1) is a multitransmembrane domainspanning endoplasmic reticulum (ER)-located protein that is evolutionarily conserved and protects against apoptosis and ER stress. Furthermore, BI-1 is proposed to modulate ER Ca 2؉homeostasis by acting as a Ca 2؉ -leak channel. Based on experimental determination of the BI-1 topology, we propose that its C terminus forms a Ca 2؉ pore responsible for its Ca 2؉ -leak properties. We utilized a set of C-terminal peptides to screen for Ca 2؉ leak activity in unidirectional 45 Ca 2؉ -flux experiments and identified an ␣-helical 20-amino acid peptide causing Ca 2؉ leak from the ER. The Ca 2؉ leak was independent of endogenous ER Ca 2؉ -release channels or other Ca 2؉ -leak mechanisms, namely translocons and presenilins. The Ca 2؉ -permeating property of the peptide was confirmed in lipid-bilayer experiments. Using mutant peptides, we identified critical residues responsible for the Ca 2؉ -leak properties of this BI-1 peptide, including a series of critical negatively charged aspartate residues. Using peptides corresponding to the equivalent BI-1 domain from various organisms, we found that the Ca 2؉ -leak properties were conserved among animal, but not plant and yeast orthologs. By mutating one of the critical aspartate residues in the proposed Ca 2؉ -channel pore in full-length BI-1, we found that Asp-213 was essential for BI-1-dependent ER Ca 2؉ leak. Thus, we elucidated residues critically important for BI-1-mediated Ca 2؉ leak and its potential channel pore. Remarkably, one of these residues was not conserved among plant and yeast BI-1 orthologs, indicating that the ER Ca2؉ -leak properties of BI-1 are an added function during evolution. leak from the ER (9, 10). BI-1 seems to be strongly evolutionarily conserved and BI-1 orthologs from plants can substitute for mammalian BI-1 in regard to its anti-apoptotic function (11). Besides this, other diverse functions of BI-1 have been described. BI-1 is a negative regulator of the ER-stress sensor (12), it interacts with G-actin and increases actin polymerization (13), enhances cancer metastasis by altering glucose metabolism and by activating a sodium-hydrogen exchanger (14), and it reduces production of reactive oxygen species through direct interaction with NADPH-P450 reductase (15), a member of the microsomal monooxygenase system.Recently, the role of BI-1 in Ca 2ϩ signaling has been further explored. The effect of BI-1 on cell death seems to involve changes in the amount of Ca 2ϩ that is releasable from intrace...

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Section: The Endoplasmic Reticulum (Er)mentioning

confidence: 99%

“…2B). The concentrationdependent effects of CTP1 on the Ca 2ϩ leak were obtained by adding different concentrations of CTP1 (5,10,20,40, and 80 M) after 10 min of efflux (Fig. 2C).…”

Section: A C-terminal Peptide Representing the Putative Pore Domain Omentioning

confidence: 99%

The C Terminus of Bax Inhibitor-1 Forms a Ca2+-permeable Channel Pore

Bultynck

Kiviluoto

Henke

et al. 2012

Journal of Biological Chemistry

Self Cite

102

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“…Connexin (Cx) subunits are the building blocks of vertebrate gap junction channels [110][111][112][113]. More than 20 human connexin isoforms have been identified, with predicted size of individual species ranging from 23 to 62 kDa and, accordingly, referred as to Cxn, where n denotes the molecular weight (e.g., Cx30, Cx43).…”

Section: Connexinsmentioning

confidence: 99%

Vesicular and conductive mechanisms of nucleotide release

Lazarowski

2012

Purinergic Signalling

252

225

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Extracellular nucleotides and nucleosides promote a vast range of physiological responses, via activation of cell surface purinergic receptors. Virtually all tissues and cell types exhibit regulated release of ATP, which, in many cases, is accompanied by the release of uridine nucleotides. Given the relevance of extracellular nucleotide/nucleoside-evoked responses, understanding how ATP and other nucleotides are released from cells is an important physiological question. By facilitating the entry of cytosolic nucleotides into the secretory pathway, recently identified vesicular nucleotide and nucleotide-sugar transporters contribute to the exocytotic release of ATP and UDP-sugars not only from endocrine/exocrine tissues, but also from cell types in which secretory granules have not been biochemically characterized. In addition, plasma membrane connexin hemichannels, pannexin channels, and less-well molecularly defined ATP conducting anion channels have been shown to contribute to the release of ATP (and UTP) under a variety of conditions.

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“…[17][18][19] Pannexins are related to the Cx-protein family: they have a similar topology but no sequence homology with Cxs and form plasma membrane channels that, like Cx-hemichannels, are Ca 2þ -permeable and function as ATP release channels. 20,21 Panx1 is expressed in SMCs of resistance arteries in several vascular beds 22 and plays a role in the vasoconstriction induced by a1-adrenergic stimulation of thoracodorsal arteries. 23, 24 Here we aimed to investigate whether Cx-hemichannels are involved in SMC Ca 2þ oscillations and control of vascular tone.…”

Section: Introductionmentioning

confidence: 99%