Browsing by Author "Orellana, Juan A."
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Item Cell membrane permeabilization via connexin hemichannels in living and dying cells(2010) Sáez, Juan C.; Schalper, Kurt A.; Retamal, Mauricio A.; Orellana, Juan A.; Shoji, Kenji F.; Bennett, Michael V.LVertebrate cells that express connexins likely express connexin hemichannels (Cx HCs) at their surface. In diverse cell types, surface Cx HCs can open to serve as a diffusional exchange pathway for ions and small molecules across the cell membrane. Most cells, if not all, also express pannexins that form hemichannels and increase the cell membrane permeability but are not addressed in this review. To date, most characterizations of Cx HCs have utilized cultured cells under resting conditions have and revealed low open probability and unitary conductance close to double that of the corresponding gap junction channels. In addition, the cell membrane permeability through Cx HCs can be markedly affected within seconds to minutes by various changes in the intra and/or extracellular microenvironment (i.e., pH, pCa, redox state, transmembrane voltage and intracellular regulatory proteins) that affect levels, open probability and/or (single channel) permeability of Cx HC. Net increase or decrease in membrane permeability could result from the simultaneous interaction of different mechanisms that affect hemichannels. The permeability of Cx HCs is controlled by complex signaling cascades showing connexin, cell and cell stage dependency. Changes in membrane permeability via hemichannels can have positive consequences in some cells (mainly in healthy cells), whereas in others (mainly in cells affected by acquired and/or genetic diseases) hemichannel activation can be detrimental.Item Interferon-γ and high glucose-induced opening of Cx43 hemichannels causes endothelial cell dysfunction and damage(2020) Sáez, Juan C.; Contreras-Duarte, Susana; Labra, Valeria C.; Santibañez, Cristian A.; Mellado, Luis A.; Inostroza, Carla A.; Alvear, Tanhia F.; Retamal, Mauricio; Velarde, Victoria; Orellana, Juan A.Both IFN-γ or high glucose have been linked to systemic inflammatory imbalance with serious repercussions not only for endothelial function but also for the formation of the atherosclerotic plaque. Although the uncontrolled opening of connexin hemichannels underpins the progression of various diseases, whether they are implicated in endothelial cell dysfunction and damage evoked by IFN-γ plus high glucose remains to be fully elucidated. In this study, by using live cell imaging and biochemical approaches, we demonstrate that IFN-γ plus high glucose augment endothelial connexin43 hemichannel activity, resulting in the increase of ATP release, ATP-mediated Ca2+ dynamics and production of nitric oxide and superoxide anion, as well as impaired insulin-mediated uptake and intercellular diffusion of glucose and cell survival. Based on our results, we propose that connexin 43 hemichannel inhibition could serve as a new approach for tackling the activation of detrimental signaling resulting in endothelial cell dysfunction and death caused by inflammatory mediators during atherosclerosis secondary to diabetes mellitusItem Synaptic Functions of Hemichannels and Pannexons: A Double-Edged Sword(2018) Abudara, Verónica; Retamal, Mauricio; Del Rio, Rodrigo; Orellana, Juan A.The classical view of synapses as the functional contact between presynaptic and postsynaptic neurons has been challenged in recent years by the emerging regulatory role of glial cells. Astrocytes, traditionally considered merely supportive elements are now recognized as active modulators of synaptic transmission and plasticity at the now so-called “tripartite synapse.” In addition, an increasing body of evidence indicates that beyond immune functions microglia also participate in various processes aimed to shape synaptic plasticity. Release of neuroactive compounds of glial origin, -process known as gliotransmission-, constitute a widespread mechanism through which glial cells can either potentiate or reduce the synaptic strength. The prevailing vision states that gliotransmission depends on an intracellular Ca2C/exocytotic-mediated release; notwithstanding, growing evidence is pointing at hemichannels (connexons) and pannexin channels (pannexons) as alternative non-vesicular routes for gliotransmitters efflux. In concurrence with this novel concept, both hemichannels and pannexons are known to mediate the transfer of ions and signaling molecules -such as ATP and glutamate- between the cytoplasm and the extracellular milieu. Importantly, recent reports show that glial hemichannels and pannexons are capable to perceive synaptic activity and to respond to it through changes in their functional state. In this article, we will review the current information supporting the “double edge sword” role of hemichannels and pannexons in the function of central and peripheral synapses. At one end, available data support the idea that these channels are chief components of a feedback control mechanism through which gliotransmitters adjust the synaptic gain in either resting or stimulated conditions. At the other end, we will discuss how the excitotoxic release of gliotransmitters and [Ca2C] overload linked to the opening of hemichannels/pannexons might impact cell function and survival in the nervous system