Differentiating connexin hemichannels and pannexin channels in cellular ATP release

Lohman, Alexander W.; Isakson, Brant E.

doi:10.1016/j.febslet.2014.02.004

Cited by 158 publications

(175 citation statements)

References 141 publications

(204 reference statements)

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“…One explanation for this discrepancy may be that Panx1 shRNAs or YoPro-1 concentrations used here were not optimal. Based on our recent work and the literature, there are several mechanisms for eATP release and YoPro-1 uptake in liver cells [48][49][50]. Although Panx1 can act in a receptor-independent fashion, it is equally possible that Panx1 pore formation is operating by a P2X7 receptor-driven mechanism [51][52][53].…”

Section: Discussionmentioning

confidence: 99%

Lipoapoptosis induced by saturated free fatty acids stimulates monocyte migration: a novel role for Pannexin1 in liver cells

Xiao

Waldrop

Bronk

et al. 2015

Purinergic Signalling

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Recruitment of monocytes in the liver is a key pathogenic feature of hepatic inflammation in nonalcoholic steatohepatitis (NASH), but the mechanisms involved are poorly understood. Here, we studied migration of human monocytes in response to supernatants obtained from liver cells after inducing lipoapoptosis with saturated free fatty acids (FFA). Lipoapoptotic supernatants stimulated monocyte migration with the magnitude similar to a monocyte chemoattractant protein, CCL2 (MCP-1). Inhibition of c-Jun NH 2 -terminal kinase (JNK) in liver cells with SP600125 blocked migration of monocytes in a dose-dependent manner, indicating that JNK stimulates release of chemoattractants in lipoapoptosis. Notably, treatment of supernatants with Apyrase to remove ATP potently inhibited migration of THP-1 monocytes and partially blocked migration of primary human monocytes. Inhibition of the CCL2 receptor (CCR2) on THP-1 monocytes with RS102895, a specific CCR2 inhibitor, did not block migration induced by lipoapoptotic supernatants. Consistent with these findings, lipoapoptosis stimulated pathophysiological extracellular ATP (eATP) release that increased supernatant eATP concentration from 5 tõ 60 nM. Importantly, inhibition of Panx1 expression in liver cells with short hairpin RNA (shRNA) decreased supernatant eATP concentration and inhibited monocyte migration, indicating that monocyte migration is mediated in part by Panx1-dependent eATP release. Moreover, JNK inhibition decreased supernatant eATP concentration and inhibited Pannexin1 activation, as determined by YoPro-1 uptake in liver cells in a dose-dependent manner. These results suggest that JNK regulates activation of Panx1 channels, and provide evidence that Pannexin1-dependent pathophysiological eATP release in lipoapoptosis is capable of stimulating migration of human monocytes, and may participate in the recruitment of monocytes in chronic liver injury induced by saturated FFA.

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Section: Discussionmentioning

confidence: 99%

Lipoapoptosis induced by saturated free fatty acids stimulates monocyte migration: a novel role for Pannexin1 in liver cells

Xiao

Waldrop

Bronk

et al. 2015

Purinergic Signalling

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“…Both have a wide spectrum of effects, but it is known that probenecid has more potent effects on pannexin than on connexin, whereas octanol is relatively specific for connexin (Silverman et al, 2008;Lohman and Isakson, 2014). Each reagent reduced the stretch-induced Ca 2+ responses by less than half, although probenecid was somewhat more potent (supplementary material Fig.…”

Section: Fig 7 the Inhibitory Effects Of Various Inhibitors Of Atp-camentioning

confidence: 99%

Mechanosensitive ATP release from hemichannels and Ca2+ influx through TRPC6 accelerate wound closure in keratinocytes

Takada

Furuya

Sokabe

2014

Journal of Cell Science

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Cutaneous wound healing is accelerated by exogenous mechanical forces and is impaired in TRPC6-knockout mice. Therefore, we designed experiments to determine how mechanical force and TRPC6 channels contribute to wound healing using HaCaT keratinocytes. HaCaT cells were pretreated with hyperforin, a major component of a traditional herbal medicine for wound healing and also a TRPC6 activator, and cultured in an elastic chamber. At 3 h after scratching the confluent cell layer, the ATP release and intracellular Ca 2+ increases in response to stretching (20%) were live-imaged. ATP release was observed only in cells at the frontier facing the scar. The diffusion of released ATP caused intercellular Ca 2+ waves that propagated towards the rear cells in a P2Y-receptor-dependent manner. The Ca 2+ response and wound healing were inhibited by ATP diphosphohydrolase apyrase, the P2Y antagonist suramin, the hemichannel blocker CBX and the TRPC6 inhibitor diC8-PIP 2 . Finally, the hemichannel-permeable dye calcein was taken up only by ATP-releasing cells. These results suggest that stretch-accelerated wound closure is due to the ATP release through mechanosensitive hemichannels from the foremost cells and the subsequent Ca 2+ waves mediated by P2Y and TRPC6activation.

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“…These metabolic pathways traced to mitochondria. Mitochondria are responsible for initiating and coordinating innate immunity18 and produce stereotyped changes in oxidative metabolism under stress19 that lead to the regulated release of purine and pyrimidine nucleotides like ATP and UTP through cell membrane channels 20. Inside the cell, ATP is an energy carrier.…”

Section: Introductionmentioning

confidence: 99%

Low‐dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial

Naviaux

Curtis

et al. 2017

Ann Clin Transl Neurol

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ObjectiveNo drug is yet approved to treat the core symptoms of autism spectrum disorder (ASD). Low‐dose suramin was effective in the maternal immune activation and Fragile X mouse models of ASD. The Suramin Autism Treatment‐1 (SAT‐1) trial was a double‐blind, placebo‐controlled, translational pilot study to examine the safety and activity of low‐dose suramin in children with ASD.MethodsTen male subjects with ASD, ages 5–14 years, were matched by age, IQ, and autism severity into five pairs, then randomized to receive a single, intravenous infusion of suramin (20 mg/kg) or saline. The primary outcomes were ADOS‐2 comparison scores and Expressive One‐Word Picture Vocabulary Test (EOWPVT). Secondary outcomes were the aberrant behavior checklist, autism treatment evaluation checklist, repetitive behavior questionnaire, and clinical global impression questionnaire.ResultsBlood levels of suramin were 12 ± 1.5 μmol/L (mean ± SD) at 2 days and 1.5 ± 0.5 μmol/L after 6 weeks. The terminal half‐life was 14.7 ± 0.7 days. A self‐limited, asymptomatic rash was seen, but there were no serious adverse events. ADOS‐2 comparison scores improved by −1.6 ± 0.55 points (n = 5; 95% CI = −2.3 to −0.9; Cohen's d = 2.9; P = 0.0028) in the suramin group and did not change in the placebo group. EOWPVT scores did not change. Secondary outcomes also showed improvements in language, social interaction, and decreased restricted or repetitive behaviors.InterpretationThe safety and activity of low‐dose suramin showed promise as a novel approach to treatment of ASD in this small study.

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Differentiating connexin hemichannels and pannexin channels in cellular ATP release

Cited by 158 publications

References 141 publications

Lipoapoptosis induced by saturated free fatty acids stimulates monocyte migration: a novel role for Pannexin1 in liver cells

Lipoapoptosis induced by saturated free fatty acids stimulates monocyte migration: a novel role for Pannexin1 in liver cells

Mechanosensitive ATP release from hemichannels and Ca2+ influx through TRPC6 accelerate wound closure in keratinocytes

Low‐dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial

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