Intercellular calcium (Ca
2+
) waves (ICWs) represent the propagation of increases in intracellular Ca
2+
through a syncytium of cells and appear to be a fundamental mechanism for coordinating ...multicellular responses. ICWs occur in a wide diversity of cells and have been extensively studied in vitro. More recent studies focus on ICWs in vivo. ICWs are triggered by a variety of stimuli and involve the release of Ca
2+
from internal stores. The propagation of ICWs predominately involves cell communication with internal messengers moving via gap junctions or extracellular messengers mediating paracrine signaling. ICWs appear to be important in both normal physiology as well as pathophysiological processes in a variety of organs and tissues including brain, liver, retina, cochlea, and vascular tissue. We review here the mechanisms of initiation and propagation of ICWs, the key intra- and extracellular messengers (inositol 1,4,5-trisphosphate and ATP) mediating ICWs, and the proposed physiological functions of ICWs.
Hunting for connexin hemichannels Sáez, Juan C.; Leybaert, Luc
FEBS letters,
April 17, 2014, Letnik:
588, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Connexin hemichannels (connexons) are building blocks of gap junctions but also function as free unapposed channels, which has become an active field of research. Defining functions of hemichannels ...and their involvement in any biological event requires ruling out possible participation of other channels that share biophysical and regulatory properties, for example pannexins, CALHM1 and P2X receptors. The lack of specific inhibitors for these channels has become an obstacle in elucidating the role of connexin hemichannels. Several experimental approaches are now available to identify hemichannels at the cell surface and to characterize their electrophysiological, permeability and regulatory properties. The use of connexin knockout/knockdown, and the development of peptides that target intracellular connexin domains and specific antibodies directed to extracellular domains have helped to dissect the role of hemichannels in endogenously expressing systems. Moreover, studies of connexin mutants in exogenous expression systems have provided convincing evidence on hemichannels in the pathogenesis of several human genetic diseases. We here present a brief overview of connexin hemichannels as functional channels and itemize a list of aspects to consider when concluding on their involvement.
Radiotherapy is an effective treatment for breast cancer and other thoracic tumors. However, while high-energy radiotherapy treatment successfully kills cancer cells, radiation exposure of the heart ...and large arteries cannot always be avoided, resulting in secondary cardiovascular disease in cancer survivors. Radiation-induced changes in the cardiac vasculature may thereby lead to coronary artery atherosclerosis, which is a major cardiovascular complication nowadays in thoracic radiotherapy-treated patients. The underlying biological and molecular mechanisms of radiation-induced atherosclerosis are complex and still not fully understood, resulting in potentially improper radiation protection. Ionizing radiation (IR) exposure may damage the vascular endothelium by inducing DNA damage, oxidative stress, premature cellular senescence, cell death and inflammation, which act to promote the atherosclerotic process. Intercellular communication mediated by connexin (Cx)-based gap junctions and hemichannels may modulate IR-induced responses and thereby the atherosclerotic process. However, the role of endothelial Cxs and their channels in atherosclerotic development after IR exposure is still poorly defined. A better understanding of the underlying biological pathways involved in secondary cardiovascular toxicity after radiotherapy would facilitate the development of effective strategies that prevent or mitigate these adverse effects. Here, we review the possible roles of intercellular Cx driven signaling and communication in radiation-induced atherosclerosis.
Over the past several decades a large amount of data have established that glial cells, the main cell population in the brain, dynamically interact with neurons and thus impact their activity and ...survival. One typical feature of glia is their marked expression of several connexins, the membrane proteins forming intercellular gap junction channels and hemichannels. Pannexins, which have a tetraspan membrane topology as connexins, are also detected in glial cells. Here, we review the evidence that connexin and pannexin channels are actively involved in dynamic and metabolic neuroglial interactions in physiological as well as in pathological situations. These features of neuroglial interactions open the way to identify novel non-neuronal aspects that allow for a better understanding of behavior and information processing performed by neurons. This will also complement the "neurocentric" view by facilitating the development of glia-targeted therapeutic strategies in brain disease.
Connexins are widely distributed proteins in the body that are crucially important for heart and brain functions. Six connexin subunits form a connexon or hemichannel in the plasma membrane. ...Interactions between two hemichannels in a head-to-head arrangement result in the formation of a gap junction channel. Gap junctions are necessary to coordinate cell function by passing electrical current flow between heart and nerve cells or by allowing exchange of chemical signals and energy substrates. Apart from its localization at the sarcolemma of cardiomyocytes and brain cells, connexins are also found in the mitochondria where they are involved in the regulation of mitochondrial matrix ion fluxes and respiration. Connexin expression is affected by age and gender as well as several pathophysiological alterations such as hypertension, hypertrophy, diabetes, hypercholesterolemia, ischemia, post-myocardial infarction remodeling or heart failure, and post-translationally connexins are modified by phosphorylation/de-phosphorylation and nitros(yl)ation which can modulate channel activity. Using knockout/knockin technology as well as pharmacological approaches, one of the connexins, namely connexin 43, has been identified to be important for cardiac and brain ischemia/reperfusion injuries as well as protection from it. Therefore, the current review will focus on the importance of connexin 43 for irreversible injury of heart and brain tissues following ischemia/reperfusion and will highlight the importance of connexin 43 as an emerging therapeutic target in cardio- and neuroprotection.
Summary
Necroptosis is one the best‐characterized forms of regulated necrosis. Necroptosis is mediated by the kinase activities of receptor interacting protein kinase‐1 and receptor interacting ...protein kinase‐3, which eventually lead to the activation of mixed lineage kinase domain‐like. Necroptosis is characterized by rapid permeabilization of the plasma membrane, which is associated with the release of the cell content and subsequent exposure of damage‐associated molecular patterns (DAMPs) and cytokines/chemokines. This release underlies the immunogenic nature of necroptotic cancer cells and their ability to induce efficient anti‐tumor immunity. Triggering necroptosis has become especially important in experimental cancer treatments as an alternative to triggering apoptosis because one of the hallmarks of cancer is the blockade or evasion of apoptosis. In this review, we discuss recent advances in necroptosis research and the functional consequences of necroptotic cancer cell death, with focus on its immunogenicity and its role in the activation of anti‐tumor immunity. Next, we discuss the molecular mechanisms of phosphatidylserine exposure during necroptosis and its role in the recognition of necroptotic cells. We also highlight the complex role of the necroptotic pathway in tumor promotion and suppression and in metastasis. Future studies will show whether necroptosis is truly a better strategy to overcome apoptosis resistance and provide the insights needed for development of novel treatment strategies for cancer.
Neurovascular and neurometabolic coupling help the brain to maintain an appropriate energy flow to the neural tissue under conditions of increased neuronal activity. Both coupling phenomena provide ...us, in addition, with two macroscopically measurable parameters, blood flow and intermediate metabolite fluxes, that are used to dynamically image the functioning brain. The main energy substrate for the brain is glucose, which is metabolized by glycolysis and oxidative breakdown in both astrocytes and neurons. Neuronal activation triggers increased glucose consumption and glucose demand, with new glucose being brought in by stimulated blood flow and glucose transport over the blood-brain barrier. Glucose is shuttled over the barrier by the GLUT-1 transporter, which, like all transporter proteins, has a ceiling above which no further stimulation of the transport is possible. Blood-brain barrier glucose transport is generally accepted as a nonrate-limiting step but to prevent it from becoming rate-limiting under conditions of neuronal activation, it might be necessary for the transport parameters to be adapted to the increased glucose demand. It is proposed that the blood-brain barrier glucose transport parameters are dynamically adapted to the increased glucose needs of the neural tissue after activation according to a neurobarrier coupling scheme. This review presents neurobarrier coupling within the current knowledge on neurovascular and neurometabolic coupling, and considers arguments and evidence in support of this hypothesis.
Astrocytes interact dynamically with neurons by modifying synaptic activity and plasticity. This interplay occurs through a process named gliotransmission, meaning that neuroactive molecules are ...released by astrocytes. Acting as a gliotransmitter, D-serine, a co-agonist of the NMDA receptor at the glycine-binding site, can be released by astrocytes in a calcium Ca
-dependent manner. A typical feature of astrocytes is their high expression level of connexin43 (Cx43), a protein forming gap junction channels and hemichannels associated with dynamic neuroglial interactions. Pharmacological and genetic inhibition of Cx43 hemichannel activity reduced the amplitude of NMDA EPSCs in mouse layer 5 prefrontal cortex pyramidal neurons without affecting AMPA EPSC currents. This reduction of NMDA EPSCs was rescued by addition of D-serine in the extracellular medium. LTP of NMDA and AMPA EPSCs after high-frequency stimulation was reduced by prior inhibition of Cx43 hemichannel activity. Inactivation of D-serine synthesis within the astroglial network resulted in the reduction of NMDA EPSCs, which was rescued by adding extracellular D-serine. We showed that the activity of Cx43 hemichannels recorded in cultured astrocytes was Ca
dependent. Accordingly, in acute cortical slices, clamping Ca
at a low level in astroglial network resulted in an inhibition of NMDA EPSC potentiation that was rescued by adding extracellular D-serine. This work demonstrates that astroglial Cx43 hemichannel activity is associated with D-serine release. This process, occurring by direct permeation of D-serine through hemichannels or indirectly by Ca
entry and activation of other Ca
-dependent mechanisms results in the modulation of synaptic activity and plasticity.
We recorded neuronal glutamatergic (NMDA and AMPA) responses in prefrontal cortex (PFC) neurons and used pharmacological and genetic interventions to block connexin-mediated hemichannel activity specifically in a glial cell population. For the first time in astrocytes, we demonstrated that hemichannel activity depends on the intracellular calcium concentration and is associated with D-serine release. Blocking hemichannel activity reduced the LTP of these excitatory synaptic currents triggered by high-frequency stimulation. These observations may be particularly relevant in the PFC, where D-serine and its converting enzyme are highly expressed.
Calcium (Ca
) signalling plays an indispensable role in dental pulp and dentin regeneration, but the Ca
responses of human dental pulp stem cells (hDPSCs) stimulated with tricalcium silicate-based ...(TCS-based) dental biomaterials remains largely unexplored. The objective of the present study was to identify and correlate extracellular Ca
concentration, intracellular Ca
dynamics, pH, cytotoxicity, gene expression and mineralization ability of human dental pulp stem cells (hDPSCs) stimulated with two different TCS-based biomaterials: Biodentine and ProRoot white MTA. The hDPSCs were exposed to the biomaterials, brought in contact with the overlaying medium, with subsequent measurements of extracellular Ca
and pH, and intracellular Ca
changes. Messenger RNA expression (BGLAP, TGF-β, MMP1 and BMP2), cytotoxicity (MTT and TUNEL) and mineralization potential (Alizarin red and Von Kossa staining) were then evaluated. Biodentine released significantly more Ca
in the α-MEM medium than ProRoot WMTA but this had no cytotoxic impact on hDPSCs. The larger Biodentine-linked Ca
release resulted in altered intracellular Ca
dynamics, which attained a higher maximum amplitude, faster rise time and increased area under the curve of the Ca
changes compared to ProRoot WMTA. Experiments with intracellular Ca
chelation, demonstrated that the biomaterial-triggered Ca
dynamics affected stem cell-related gene expression, cellular differentiation and mineralization potential. In conclusion, biomaterial-specific Ca
dynamics in hDPSCs determine differentiation and mineralization outcomes, with increased Ca
dynamics enhancing mineralization.
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