Contribution of Pannexin 1 and Connexin 43 Hemichannels to Extracellular Calcium–Dependent Transport Dynamics in Human Blood-Brain Barrier Endothelial Cells

Kaneko, Yosuke; Tachikawa, Masanori; Akaogi, Ryo; Fujimoto, Kazuhisa; Ishibashi, Masayoshi; Uchida, Yasuo; Couraud, Pierre Olivier; Ohtsuki, Sumio; Hosoya, Ken; Terasaki, Tetsuya

doi:10.1124/jpet.114.220210

Cited by 37 publications

(37 citation statements)

References 36 publications

(37 reference statements)

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“…The resealing of BTB is likely mediated by Cx43‐induced F‐actin reorganization, possibly involving p‐FAK‐Tyr 407 as noted herein, which is an important regulator of actin nucleation at the basal ES of the BTB (25). These findings are also in agreement with recent reports that Cx43 and other GJ proteins play a crucial role on the integrity and function of other tissue barriers such as the blood—brain barrier (39) and epidermal barrier (40). Furthermore, the percentage of tubules that had their disrupted BTB resealed was estimated to be ~25% as shown in Fig.…”

Section: Discussionsupporting

confidence: 93%

Connexin 43 reboots meiosis and reseals blood‐testis barrier following toxicant‐mediated aspermatogenesis and barrier disruption

Li¹,

Mruk²,

Mok³

et al. 2015

FASEB j.

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Earlier studies have shown that rats treated with an acute dose of 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (adjudin, a male contraceptive under development) causes permanent infertility due to irreversible blood-testis barrier (BTB) disruption even though the population of undifferentiated spermatogonia remains similar to normal rat testes, because spermatogonia fail to differentiate into spermatocytes to enter meiosis. Since other studies have illustrated the significance of connexin 43 (Cx43)-based gap junction in maintaining the homeostasis of BTB in the rat testis and the phenotypes of Sertoli cell-conditional Cx43 knockout mice share many of the similarities of the adjudin-treated rats, we sought to examine if overexpression of Cx43 in these adjudin-treated rats would reseal the disrupted BTB and reinitiate spermatogenesis. A full-length Cx43 cloned into mammalian expression vector pCI-neo was used to transfect testes of adjudin-treated ratsversusempty vector. It was found that overexpression of Cx43 indeed resealed the Sertoli cell tight junction-permeability barrier based on a functionalin vivoassay in tubules displaying signs of meiosis as noted by the presence of round spermatids. Thus, these findings suggest that overexpression of Cx43 reinitiated spermatogenesis at least through the steps of meiosis to generate round spermatids in testes of rats treated with an acute dose of adjudin that led to aspermatogenesis. It was also noted that the round spermatids underwent eventual degeneration with the formation of multinucleated cells following Cx43 overexpression due to the failure of spermiogenesis because no elongating/elongated spermatids were detected in any of the tubules examined. The mechanism by which overexpression of Cx43 reboots meiosis and rescues BTB function was also examined. In summary, overexpression of Cx43 in the testis with aspermatogenesis reboots meiosis and reseals toxicant-induced BTB disruption, even though it fails to support round spermatids to enter spermiogenesis.-Li, N., Mruk, D. D., Mok, K.-W., Li, M. W. M., Wong, C. K. C., Lee, W. M., Han, D., Silvestrini, B., Cheng, C. Y. Connexin 43 reboots meiosis and reseals blood-testis barrier following toxicant-mediated aspermatogenesis and barrier disruption.

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Section: Discussionsupporting

confidence: 93%

Connexin 43 reboots meiosis and reseals blood‐testis barrier following toxicant‐mediated aspermatogenesis and barrier disruption

Li¹,

Mruk²,

Mok³

et al. 2015

FASEB j.

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“…As such, endothelial HCs provide a novel target to limit endothelial barrier disruption in inflammatory and ischemia-reperfusion conditions. More recently, Panx2 expression has been suggested to be present in endothelial cells in the rat middle cerebral artery [379], while Panx1 expression was identified in a human brain microvascular endothelial cell line [380]. Removal of extracellular calcium appeared to open both Cx43 HCs and Panx1 channels in the microvascular endothelial cells, which is in marked contrast to previous findings that Panx1 channels are insensitive to changes in [Ca 2? ]…”

Section: Endothelial Connexins and Endothelial Barrier Functioncontrasting

confidence: 55%

“…e [55,76]. In addition, drugs that act neuroprotective in animal ischemia models inhibited the activation of these channels [380]. These pioneer studies highlight the importance of endothelial Cxs and Panxs in BBB functioning and provide an incentive to further investigate their exact mechanistic contribution in modulating BBB integrity in physiology and pathology.…”

Section: Endothelial Connexins and Endothelial Barrier Functionmentioning

confidence: 99%

Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

Decrock

Bock

Wang

et al. 2015

Cell. Mol. Life Sci.

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The central nervous system (CNS) is composed of a highly heterogeneous population of cells. Dynamic interactions between different compartments (neuronal, glial, and vascular systems) drive CNS function and allow to integrate and process information as well as to respond accordingly. Communication within this functional unit, coined the neuro-glio-vascular unit (NGVU), typically relies on two main mechanisms: direct cell-cell coupling via gap junction channels (GJCs) and paracrine communication via the extracellular compartment, two routes to which channels composed of transmembrane connexin (Cx) or pannexin (Panx) proteins can contribute. Multiple isoforms of both protein families are present in the CNS and each CNS cell type is characterized by a unique Cx/Panx portfolio. Over the last two decades, research has uncovered a multilevel platform via which Cxs and Panxs can influence different cellular functions within a tissue: (1) Cx GJCs enable a direct cell-cell communication of small molecules, (2) Cx hemichannels and Panx channels can contribute to autocrine/paracrine signaling pathways, and (3) different structural domains of these proteins allow for channel-independent functions, such as cell-cell adhesion, interactions with the cytoskeleton, and the activation of intracellular signaling pathways. In this paper, we discuss current knowledge on their multifaceted contribution to brain development and to specific processes in the NGVU, including synaptic transmission and plasticity, glial signaling, vasomotor control, and blood-brain barrier integrity in the mature CNS. By highlighting both physiological and pathological conditions, it becomes evident that Cxs and Panxs can play a dual role in the CNS and that an accurate fine-tuning of each signaling mechanism is crucial for normal CNS physiology.

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“…124 However, there is no data regarding phosphorylation modifications of Cx43 in brain endothelial cells and other neurovascular components, although alterations in Cx43 expression are indicated in BBB dysfunction including vasogenic edema formation, alterations in transporters expression and leukocyte migration. 125,126 Palmitoylation, methylation and glycosylation Palmitoylation is the covalent modification of proteins with lipids (fatty acids) via thioester linkage to Cys residues. This is a reversible process and palmitoylation/depalmitoylation can regulate cellular functions including: membrane association of soluble proteins, protein-protein interactions, protein trafficking, subcellular targeting, partitioning of proteins into specific membrane domains, and it changes protein structure and stability.…”

Section: Phosphorylationmentioning

confidence: 99%

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

et al. 2016

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Contribution of Pannexin 1 and Connexin 43 Hemichannels to Extracellular Calcium–Dependent Transport Dynamics in Human Blood-Brain Barrier Endothelial Cells

Cited by 37 publications

References 36 publications

Connexin 43 reboots meiosis and reseals blood‐testis barrier following toxicant‐mediated aspermatogenesis and barrier disruption

Connexin 43 reboots meiosis and reseals blood‐testis barrier following toxicant‐mediated aspermatogenesis and barrier disruption

Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

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