Estrogen deficiency in postmenopausal women is a major cause of bone loss,resulting in osteopenia,osteoporosis,and a high risk for bone fracture.Connexin 43 (Cx43) hemichannels (HCs) in osteocytes play an important ro...Estrogen deficiency in postmenopausal women is a major cause of bone loss,resulting in osteopenia,osteoporosis,and a high risk for bone fracture.Connexin 43 (Cx43) hemichannels (HCs) in osteocytes play an important role in osteocyte viability,bone formation,and remodeling.We showed here that estrogen deficiency reduced Cx43 expression and HC function.To determine if functional HCs protect osteocytes and bone loss during estrogen deficiency,we adopted an ovariectomy model in wild-type (WT) and two transgenic Cx43 mice:R76W (dominant-negative mutant inhibiting only gap junction channels) and Cx43 Δ130–136 (dominant-negative mutant compromising both gap junction channels and HCs).The bone mineral density (BMD),bone structure,and histomorphometric changes of cortical and trabecular bones after ovariectomy were investigated.Our results showed that the Δ130–136 transgenic cohort had greatly decreased vertebral trabecular bone mass compared to WT and R76W mice,associated with a significant increase in the number of apoptotic osteocyte and empty lacunae.Moreover,osteoclast surfaces in trabecular and cortical bones were increased after ovariectomy in the R76W and WT mice,respectively,but not in Δ130–136 mice.These data demonstrate that impairment of Cx43 HCs in osteocytes accelerates vertebral trabecular bone loss and increase in osteocyte apoptosis,and further suggest that Cx43 HCs in osteocytes protect trabecular bone against catabolic effects due to estrogen deficiency.展开更多
Elevated oxidative stress （OS） during aging leads to bone loss. OS increases intracellular Ca2＋ （[Ca2＋]i）, resulting in cellular damage and death. We show earlier that Cx43 hemichannels open in response to OS, w...Elevated oxidative stress （OS） during aging leads to bone loss. OS increases intracellular Ca2＋ （[Ca2＋]i）, resulting in cellular damage and death. We show earlier that Cx43 hemichannels open in response to OS, which serves as a protective mechanism for osteocytes. However, the underlying mechanism is unknown. Here, we found that treatment with H202 increased [Ca2＋]i in osteocytes with [Ca2＋]i being primarily derived from an extracellular Ca2~ source. Hemichannel opening induced by OS was inhibited by the depletion of [Ca2＋]i with BAPTA-AM, a Ca2＋ chelator, suggesting that [Ca2＋]i influenced the activity of Cx43 hemichannels. Conversely, blockade of hemichannels had no effect on [Ca2＋]i. A biotinylation assay showed that cell surface-expressed Cx43 was increased by OS, which could be inhibited by BAPTA-AM, suggesting that [Ca2＋]i is necessary for Cx43 migration to the cell surface in response to OS. Together, these data suggest that increased hemichannel activity induced by OS was likely to be caused by elevated [Ca2＋]i through increased Cx43 on the cell surface.展开更多
Perinatal encephalopathy remains a major cause of disability, such as cerebral palsy. Therapeutic hypo- thermia is now well established to partially reduce risk of disability in late preterm/term infants. However, new...Perinatal encephalopathy remains a major cause of disability, such as cerebral palsy. Therapeutic hypo- thermia is now well established to partially reduce risk of disability in late preterm/term infants. However, new and complementary therapeutic targets are needed to further improve outcomes. There is increasing evidence that glia play a key role in neural damage after hypoxia-ischemia and infection/inflammation. In this review, we discuss the role of astrocytic gap junction （connexin） hemichannels in the spread of neural injury after hypoxia-ischemia and/or infection/inflammation. Potential mechanisms of hemichannel medi- ated injury likely involve impaired intraceUular calcium handling, loss of blood-brain barrier integrity and release of adenosine triphosphate （ATP） resulting in over-activation of purinergic receptors. We propose the hypothesis that inflammation-induced opening of connexin hemichannels is a key regulating event that initiates a vicious cycle of excessive ATP release, which in turn propagates activation of purinergic receptors on microglia and astrocytes. This suggests that developing new neuroprotective strategies for preterm infants will benefit from a detailed understanding of glial and connexin hemichannel responses.展开更多
Connexin hemichannels have long been considered asmere structural precursors for gap junctions.In the last decade,it has become clear that they also act as individual channels,connecting the intracellular compartment ...Connexin hemichannels have long been considered asmere structural precursors for gap junctions.In the last decade,it has become clear that they also act as individual channels,connecting the intracellular compartment and the extracellular environment.Impairement of connexin hemichannel functionality may result in disturbance of homeostasis,as exemplified in the current paper for the intestine and the liver.Research in this field still has a number of shortcomings,of which some are also discussed here.展开更多
Compounds that block the function of connexin and pannexin protein channels have been suggested to be valuable therapeutics for a range of diseases.Some of these compounds are now in clinical trials,but for many of th...Compounds that block the function of connexin and pannexin protein channels have been suggested to be valuable therapeutics for a range of diseases.Some of these compounds are now in clinical trials,but for many of them,the literature is inconclusive about the molecular effect on the tissue,despite evidence of functional recovery.Blocking the different channel types has distinct physiological and pathological implications and this review describes current knowledge of connexin and pannexin protein channels,their function as channels and possible mechanisms of the channel block effect for the latest therapeutic compounds.We summarize the evidence implicating pannexins and connexins in disease,considering their homeostatic versus pathological roles,their contribution to excesive ATP release linked to disease onset and progression.展开更多
OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sci...OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sciatic nerve injury(SNI)or sham surgery.Rat received daily treatment with INI-0602 intrathecally,at a dose of 0.25μg/10μL.The response frequency to mechanical allodynia in animals was measured with von Frey hairs on day 1,3,5,7,14,21.Rats were evaluated in the forced swimming test(FST)test,tail suspension test(TST),sucrose preference test(SPT)for depression-like behavior.We performed open field test(OFT)and elevated plus-maze test(EPM)to evaluate anxiety-associated behaviors.Besides,we investigated the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF)and also the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.RESULTS The SNI procedure produced mechanical allodynia and accompanied with depressive-like and anxiety-like behavior.Treatment with INI-0602 produced a significant analgesic effect in SNI rats at day 7(model+NS:11.017±1.506 g;model+INI-0602:31.157±1.532 g,P<0.01),and still obviously on the 21th day(31.067±1.787,P<0.01).INI-0602 could also improve the performance of sciatic nerve injury rats among program behavior tests related to depression and anxiety.In parallel with relief of pain,the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF),involved in central sensitization and synaptic plasticity,were investigated.INI-0602 not only could inhibited spared nerve injury induced up-regulated of NR2B and phosphorylation NR2B in early and late neuropathic pain(early phase:Nr2b:2.897±0.228,P<0.01;p-Nr2b:2.984±0.236,P<0.01;late phase:Nr2b:2.594±0.187,P<0.01;p-Nr2b:3.124±0.330,P<0.01),but also could inhibit the increased of BDNF in the early(model+NS:3.637±0.381,model+INI-0602:1.148±0.372,P<0.01)and upregulate the BDNF in late stage(model+NS:0.438±0.103,model+INI-0602:1.222±0.092,P<0.01).Meanwhile,INI-0602 significantly decreased the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.CONCLUSION INI-0602 blocked behavioral changes induced by neuropathic pain,suggesting that it might be a promising pharmacological approach of painemotion diseases.展开更多
Direct intercellular communication mediated by gap junctions constitutes a major regulatory platform in the control of hepatic homeostasis.Hepatocellular gap junctions are composed of two hemichannels of adjacent cell...Direct intercellular communication mediated by gap junctions constitutes a major regulatory platform in the control of hepatic homeostasis.Hepatocellular gap junctions are composed of two hemichannels of adjacent cells which are built up by connexin proteins,in casu Cx32.Mathieu Vinken,Pofessor at the Department of Toxicology of the Free University BrusselsBelgium,was one of the first investigators to demonstrate that hepatic connexin expression is controlled by epigenetic mechanisms.In particular,he found that inhibitors of histone deacetylase enzymes enhance Cx32 production and gap junction activity in cultures of primary hepatocytes,a finding that is of importance for liver-based in vitro modelling.Professor Dr.Mathieu Vinken's recent work is focussed on the elucidation of the role of connexin proteins and their channels in the hepatocyte life cycle.Specific attention is paid to apoptosis in this context,whereby it has been found that Cx32 hemichannels control the termination of induced cell death in cultures of primary hepatocytes. Overall,Professor Dr.Mathieu Vinken's research can be considered as an important contribution to the field of hepatic connexin physiology.展开更多
Epilepsy,a chronic neurological disorder,is characterized by dysfunction in neural networks.Gap junctions and hemichannels,which are integral to the astrocyte connection network,play a critical role in epilepsy.Connex...Epilepsy,a chronic neurological disorder,is characterized by dysfunction in neural networks.Gap junctions and hemichannels,which are integral to the astrocyte connection network,play a critical role in epilepsy.Connexins,the components of astrocyte gap junctions and hemichannels,can be activated to transfer glutamate,adenosine triphosphate,and other chemicals,potentially leading to seizures.Connexins therefore hold signifcant potential for epilepsy treatment.This review focuses on connexin 43 and provides a brief overview of other connexins and pannexin 1.Understanding the relationship between connexins and epilepsy ofers theoretical support for developing new antiseizure medications.展开更多
基金supported by NIH grants,AR072020 and CA196214Welch Foundation grant AQ-1507 to J.X.J.+1 种基金China Scholarship Council funding to L.M.Micro-CT imaging was completed at RAYO,the Daniel Carlisle Center for Bone and Mineral Imaging at the University of Texas Health Science Center at San AntonioRAYO is supported by an equipment grant.R.J.F. was supported by NIH grant RR025687
文摘Estrogen deficiency in postmenopausal women is a major cause of bone loss,resulting in osteopenia,osteoporosis,and a high risk for bone fracture.Connexin 43 (Cx43) hemichannels (HCs) in osteocytes play an important role in osteocyte viability,bone formation,and remodeling.We showed here that estrogen deficiency reduced Cx43 expression and HC function.To determine if functional HCs protect osteocytes and bone loss during estrogen deficiency,we adopted an ovariectomy model in wild-type (WT) and two transgenic Cx43 mice:R76W (dominant-negative mutant inhibiting only gap junction channels) and Cx43 Δ130–136 (dominant-negative mutant compromising both gap junction channels and HCs).The bone mineral density (BMD),bone structure,and histomorphometric changes of cortical and trabecular bones after ovariectomy were investigated.Our results showed that the Δ130–136 transgenic cohort had greatly decreased vertebral trabecular bone mass compared to WT and R76W mice,associated with a significant increase in the number of apoptotic osteocyte and empty lacunae.Moreover,osteoclast surfaces in trabecular and cortical bones were increased after ovariectomy in the R76W and WT mice,respectively,but not in Δ130–136 mice.These data demonstrate that impairment of Cx43 HCs in osteocytes accelerates vertebral trabecular bone loss and increase in osteocyte apoptosis,and further suggest that Cx43 HCs in osteocytes protect trabecular bone against catabolic effects due to estrogen deficiency.
基金supported by Welch Foundation Grant AQ-1507National Institutes of Health Grant EY012085 to JXJ
文摘Elevated oxidative stress （OS） during aging leads to bone loss. OS increases intracellular Ca2＋ （[Ca2＋]i）, resulting in cellular damage and death. We show earlier that Cx43 hemichannels open in response to OS, which serves as a protective mechanism for osteocytes. However, the underlying mechanism is unknown. Here, we found that treatment with H202 increased [Ca2＋]i in osteocytes with [Ca2＋]i being primarily derived from an extracellular Ca2~ source. Hemichannel opening induced by OS was inhibited by the depletion of [Ca2＋]i with BAPTA-AM, a Ca2＋ chelator, suggesting that [Ca2＋]i influenced the activity of Cx43 hemichannels. Conversely, blockade of hemichannels had no effect on [Ca2＋]i. A biotinylation assay showed that cell surface-expressed Cx43 was increased by OS, which could be inhibited by BAPTA-AM, suggesting that [Ca2＋]i is necessary for Cx43 migration to the cell surface in response to OS. Together, these data suggest that increased hemichannel activity induced by OS was likely to be caused by elevated [Ca2＋]i through increased Cx43 on the cell surface.
基金supported by the Health Research Council of New Zealand(grant 17/601)the Auckland Medical Research Foundation+1 种基金National Health and Medical Research Council CJ Martin Early Career Fellowship(grant No.1090890 to RG)the Victorian Government Operational Infrastructure Support Program
文摘Perinatal encephalopathy remains a major cause of disability, such as cerebral palsy. Therapeutic hypo- thermia is now well established to partially reduce risk of disability in late preterm/term infants. However, new and complementary therapeutic targets are needed to further improve outcomes. There is increasing evidence that glia play a key role in neural damage after hypoxia-ischemia and infection/inflammation. In this review, we discuss the role of astrocytic gap junction （connexin） hemichannels in the spread of neural injury after hypoxia-ischemia and/or infection/inflammation. Potential mechanisms of hemichannel medi- ated injury likely involve impaired intraceUular calcium handling, loss of blood-brain barrier integrity and release of adenosine triphosphate （ATP） resulting in over-activation of purinergic receptors. We propose the hypothesis that inflammation-induced opening of connexin hemichannels is a key regulating event that initiates a vicious cycle of excessive ATP release, which in turn propagates activation of purinergic receptors on microglia and astrocytes. This suggests that developing new neuroprotective strategies for preterm infants will benefit from a detailed understanding of glial and connexin hemichannel responses.
基金Supported partially by the Fund for Scientific Research Flanders(FWO-Vlaanderen),Belgium
文摘Connexin hemichannels have long been considered asmere structural precursors for gap junctions.In the last decade,it has become clear that they also act as individual channels,connecting the intracellular compartment and the extracellular environment.Impairement of connexin hemichannel functionality may result in disturbance of homeostasis,as exemplified in the current paper for the intestine and the liver.Research in this field still has a number of shortcomings,of which some are also discussed here.
基金supported in part by New Zealand Lottery Health Researchthe Maurice and Phyllis Paykel Trustthe New Zealand Optometric Vision Research Foundation。
文摘Compounds that block the function of connexin and pannexin protein channels have been suggested to be valuable therapeutics for a range of diseases.Some of these compounds are now in clinical trials,but for many of them,the literature is inconclusive about the molecular effect on the tissue,despite evidence of functional recovery.Blocking the different channel types has distinct physiological and pathological implications and this review describes current knowledge of connexin and pannexin protein channels,their function as channels and possible mechanisms of the channel block effect for the latest therapeutic compounds.We summarize the evidence implicating pannexins and connexins in disease,considering their homeostatic versus pathological roles,their contribution to excesive ATP release linked to disease onset and progression.
基金The project supported by National Natural Science Foundation of China(81473234,U1303221)
文摘OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sciatic nerve injury(SNI)or sham surgery.Rat received daily treatment with INI-0602 intrathecally,at a dose of 0.25μg/10μL.The response frequency to mechanical allodynia in animals was measured with von Frey hairs on day 1,3,5,7,14,21.Rats were evaluated in the forced swimming test(FST)test,tail suspension test(TST),sucrose preference test(SPT)for depression-like behavior.We performed open field test(OFT)and elevated plus-maze test(EPM)to evaluate anxiety-associated behaviors.Besides,we investigated the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF)and also the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.RESULTS The SNI procedure produced mechanical allodynia and accompanied with depressive-like and anxiety-like behavior.Treatment with INI-0602 produced a significant analgesic effect in SNI rats at day 7(model+NS:11.017±1.506 g;model+INI-0602:31.157±1.532 g,P<0.01),and still obviously on the 21th day(31.067±1.787,P<0.01).INI-0602 could also improve the performance of sciatic nerve injury rats among program behavior tests related to depression and anxiety.In parallel with relief of pain,the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF),involved in central sensitization and synaptic plasticity,were investigated.INI-0602 not only could inhibited spared nerve injury induced up-regulated of NR2B and phosphorylation NR2B in early and late neuropathic pain(early phase:Nr2b:2.897±0.228,P<0.01;p-Nr2b:2.984±0.236,P<0.01;late phase:Nr2b:2.594±0.187,P<0.01;p-Nr2b:3.124±0.330,P<0.01),but also could inhibit the increased of BDNF in the early(model+NS:3.637±0.381,model+INI-0602:1.148±0.372,P<0.01)and upregulate the BDNF in late stage(model+NS:0.438±0.103,model+INI-0602:1.222±0.092,P<0.01).Meanwhile,INI-0602 significantly decreased the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.CONCLUSION INI-0602 blocked behavioral changes induced by neuropathic pain,suggesting that it might be a promising pharmacological approach of painemotion diseases.
基金supported by grants of the FWO,the research council of the VUB and the European Union
文摘Direct intercellular communication mediated by gap junctions constitutes a major regulatory platform in the control of hepatic homeostasis.Hepatocellular gap junctions are composed of two hemichannels of adjacent cells which are built up by connexin proteins,in casu Cx32.Mathieu Vinken,Pofessor at the Department of Toxicology of the Free University BrusselsBelgium,was one of the first investigators to demonstrate that hepatic connexin expression is controlled by epigenetic mechanisms.In particular,he found that inhibitors of histone deacetylase enzymes enhance Cx32 production and gap junction activity in cultures of primary hepatocytes,a finding that is of importance for liver-based in vitro modelling.Professor Dr.Mathieu Vinken's recent work is focussed on the elucidation of the role of connexin proteins and their channels in the hepatocyte life cycle.Specific attention is paid to apoptosis in this context,whereby it has been found that Cx32 hemichannels control the termination of induced cell death in cultures of primary hepatocytes. Overall,Professor Dr.Mathieu Vinken's research can be considered as an important contribution to the field of hepatic connexin physiology.
基金supported by Natural Science Foundation of Beijing Municipality(grant number L222078)National Science Foundation of China(grant number 82071448)。
文摘Epilepsy,a chronic neurological disorder,is characterized by dysfunction in neural networks.Gap junctions and hemichannels,which are integral to the astrocyte connection network,play a critical role in epilepsy.Connexins,the components of astrocyte gap junctions and hemichannels,can be activated to transfer glutamate,adenosine triphosphate,and other chemicals,potentially leading to seizures.Connexins therefore hold signifcant potential for epilepsy treatment.This review focuses on connexin 43 and provides a brief overview of other connexins and pannexin 1.Understanding the relationship between connexins and epilepsy ofers theoretical support for developing new antiseizure medications.
