Diverse post-translational modifications of the pannexin family of channel-forming proteins

Peñuela, Silvia; Lohman, Alexander W.; Lai, Wesley; Gyenis, Laszlo; Litchfield, David W.; Isakson, Brant E.; Laird, Dale W.

doi:10.4161/chan.27422

Cited by 30 publications

(40 citation statements)

References 45 publications

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“…Future studies will examine the intracellular distribution of ATP associated with Panx1 deficiency, because it may govern ATP permeability between intracellular compartments and not just at the cell membrane. 58 In summary, we show the role of Panx1 channel as a defining factor in kidney response to IRI. Released ATP may act as a DAMP on surrounding tissue and infiltrating immune cells, allowing propagation of inflammation and injury.…”

Section: Discussionmentioning

confidence: 61%

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Jankowski¹,

Perry²,

Medina

et al. 2018

JASN

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Pannexin1 (Panx1), an ATP release channel, is present in most mammalian tissues, but the role of Panx1 in health and disease is not fully understood. Panx1 may serve to modulate AKI; ATP is a precursor to adenosine and may function to block inflammation, or ATP may act as a danger-associated molecular pattern and initiate inflammation. We used pharmacologic and genetic approaches to evaluate the effect of Panx1 on kidney ischemia-reperfusion injury (IRI), a mouse model of AKI. Pharmacologic inhibition of gap junctions, including Panx1, by administration of carbenoxolone protected mice from IRI. Furthermore, global deletion of preserved kidney function and morphology and diminished the expression of proinflammatory molecules after IRI. Analysis of bone marrow chimeric mice revealed that Panx1 expressed on parenchymal cells is necessary for ischemic injury, and both proximal tubule and vascular endothelial tissue-specific knockout mice were protected from IRI. ,-deficient proximal tubule cells released less and retained more ATP under hypoxic stress. Panx1 is involved in regulating ATP release from hypoxic cells, and reducing this ATP release may protect kidneys from AKI.

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Section: Discussionmentioning

confidence: 61%

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Jankowski¹,

Perry²,

Medina

et al. 2018

JASN

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“…[28][29][30] To assess the role of N-glycosylation in T-type channel function, we used Nglycosylation-deficient hCa v 3.2 channels where glycosylation motifs have been disrupted by mutagenesis. It was previously proposed that sialic acid residues attached to the outermost ends of glycan chains may contribute to the negative surface potential, and contributing to the gating modulation of some voltagegated Na C and K C channels by an electrostatic mechanism.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Ca_v3.2 T-type calcium channel permeability by asparagine-linked glycosylation

et al. 2016

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Low-voltage-gated T-type calcium channels are expressed throughout the nervous system where they play an essential role in shaping neuronal excitability. Defects in T-type channel expression have been linked to various neuronal disorders including neuropathic pain and epilepsy. Currently, little is known about the cellular mechanisms controlling the expression and function of T-type channels. Asparagine-linked glycosylation has recently emerged as an essential signaling pathway by which the cellular environment can control expression of T-type channels. However, the role of N-glycans in the conducting function of T-type channels remains elusive. In the present study, we used human Ca v 3.2 glycosylation-deficient channels to assess the role of N-glycosylation on the gating of the channel. Patch-clamp recordings of gating currents revealed that N-glycans attached to hCa v 3.2 channels have a minimal effect on the functioning of the channel voltage-sensor. In contrast, N-glycosylation on specific asparagine residues may have an essential role in the conducting function of the channel by enhancing the channel permeability and / or the pore opening of the channel. Our data suggest that modulation of N-linked glycosylation of hCa v 3.2 channels may play an important physiological role, and could also support the alteration of T-type currents observed in disease states.

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“…Asparagine (N)-linked glycosylation, which refers to the enzymatic attachment of glycan moieties to newly synthetized proteins, has emerged as an essential mechanism controlling ion channel function (Lazniewska and Weiss 2014). For instance, N-linked glycosylation of Ca v 1.2 and Ca v 3.2 channels is necessary for effective surface trafficking and functional expression of the channel protein (Weiss et al 2013;Park et al 2015;Ondacova et al 2016), and more generally affects expression of other ion channel families (Penuela et al 2014). In a recent study published in the Journal of Biological Chemistry, Tétreault and colleagues assessed the role of asparagine-linked glycosylation on the trafficking of α 2 δ 1 and its consequence on Ca v 1.2 channel function (Tétreault et al 2016).…”

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confidence: 99%

Glycosylation of α2δ1 subunit: a sweet talk with Cav1.2 channels

Łaźniewska

Weiss²

2016

gpb

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Bosentan, an endothelin-1 (ET) receptor antagonist is an important drug for the effective management of patients with pulmonary arterial hypertension. Bosentan has a rather complicated pharmacokinetics in humans involving multiple physiological components that have a profound influence on its drug disposition. Bosentan is mainly metabolized by cytochrome P450 (CYP) 3A4 and 2C9 enzymes with the involvement of multiple transporters that control its hepatic uptake and biliary excretion. The involvement of phase 2 metabolism of bosentan is a key to have an enhanced biliary excretion of the drug-related products. While bosentan exhibits high protein binding restricting the drug from extensive distribution and significant urinary excretion, bosentan induces its own metabolism by an increased expression of CYP3A4 on repeated dosing. Due to the above properties, bosentan has the potential to display drug-drug interaction with the co-administered drugs, either being a perpetrator or a victim. The intent of this review is manifold: a) to summarize the physiological role of CYP enzymes and hepatic-biliary transporters; b) to discuss the mechanism(s) involved in the purported liver injury caused by bosentan; c) to tabulate the numerous clinical drug-drug interaction studies involving the physiological interplay with CYP and/or transporters; d) to provide some perspectives on dosing strategy of bosentan.

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Diverse post-translational modifications of the pannexin family of channel-forming proteins

Cited by 30 publications

References 45 publications

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Modulation of Ca_v3.2 T-type calcium channel permeability by asparagine-linked glycosylation

Glycosylation of α2δ1 subunit: a sweet talk with Cav1.2 channels

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Diverse post-translational modifications of the pannexin family of channel-forming proteins

Cited by 30 publications

References 45 publications

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Modulation of Cav3.2 T-type calcium channel permeability by asparagine-linked glycosylation

Glycosylation of α2δ1 subunit: a sweet talk with Cav1.2 channels

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Modulation of Ca_v3.2 T-type calcium channel permeability by asparagine-linked glycosylation