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
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.
