Lymphatic Connexins and Pannexins in Health and Disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Ehrlich A
PROVIDER: S-EPMC8199429 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Enhanced gap junctional communication (GJC) between neurons is considered a major factor underlying the neuronal synchrony driving seizure activity. In addition, the hippocampal sharp wave ripple complexes, associated with learning and seizures, are diminished by GJC blocking agents. Although gap junctional blocking drugs inhibit experimental seizures, they all have other non-specific actions. Besides interneuronal GJC between dendrites, inter-axonal and inter-glial GJC is also considered important for seizure generation. Interestingly, in most studies of cerebral tissue from animal seizure models and from human patients with epilepsy, there is up-regulation of glial, but not neuronal gap junctional mRNA and protein. Significant changes in the expression and post-translational modification of the astrocytic connexin Cx43, and Panx1 were observed in an in vitro Co(++) seizure model, further supporting a role for glia in seizure-genesis, although the reasons for this remain unclear. Further suggesting an involvement of astrocytic GJC in epilepsy, is the fact that the expression of astrocytic Cx mRNAs (Cxs 30 and 43) is several fold higher than that of neuronal Cx mRNAs (Cxs 36 and 45), and the number of glial cells outnumber neuronal cells in mammalian hippocampal and cortical tissue. Pannexin expression is also increased in both animal and human epileptic tissues. Specific Cx43 mimetic peptides, Gap 27 and SLS, inhibit the docking of astrocytic connexin Cx43 proteins from forming intercellular gap junctions (GJs), diminishing spontaneous seizures. Besides GJs, Cx membrane hemichannels in glia and Panx membrane channels in neurons and glia are also inhibited by traditional gap junctional pharmacological blockers. Although there is no doubt that connexin-based GJs and hemichannels, and pannexin-based membrane channels are related to epilepsy, the specific details of how they are involved and how we can modulate their function for therapeutic purposes remain to be elucidated.
| S-EPMC4019879 | biostudies-literature
Project description:Connexins and pannexins are the transmembrane proteins of highly distinguished biological activity in the form of transport of molecules and electrical signals. Their common role is to connect the external environment with the cytoplasm of the cell, while connexin is also able to link two cells together allowing the transport from one to another. The analysis presented here aims to identify the similarities and differences between connexin and pannexin. As a comparative criterion, the hydrophobicity distribution in the structure of the discussed proteins was used. The comparative analysis is carried out with the use of a mathematical model, the FOD-M model (fuzzy oil drop model in its Modified version) expressing the specificity of the membrane’s external field, which in the case of the discussed proteins is significantly different from the external field for globular proteins in the polar environment of water. The characteristics of the external force field influence the structure of protein allowing the activity in a different environment.
| S-EPMC9313468 | biostudies-literature
Project description:Stable expression of pannexin 1 (Panx1) and pannexin 3 (Panx3) resulted in functional gap junctions (GJs) in HeLa cells, but not in Neuro-2a (N2a) or PC-12 cells. The glycosylation pattern of expressed Panx1 varied greatly among different cell lines. In contrast to connexin (Cx) containing GJs (Cx-GJs), junctional conductance (Gj) of pannexin GJs (Panx-GJs) is very less sensitive to junctional voltage. Both Panx1 and Panx3 junctions favoured anionic dyes over cations to permeate. Though, carbenoxolone (CBX) and probenecid blocked Panx1 hemichannel activity, they had no effect on Panx1-GJs or Panx3-GJs. Extracellular loop 1 (E1) of Panx1 possibly bears the binding pocket. The Cx-GJ blocker heptanol blocked neither Panx1 hemichannel nor Panx-GJs. Unlike the GJs formed by most Cxs, CO2 did not uncouple Panx-GJs completely. Oxygen and glucose deprivation (OGD) caused lesser uncoupling of Panx-GJs compared to Cx43-GJs. These findings demonstrate properties of Panx-GJs that are distinctly different from Cx-GJs.
| S-EPMC4021813 | biostudies-other
Project description:Evaluation of the human genome suggests that all members of the connexin family of gap-junction proteins have now been successfully identified. This large and diverse family of proteins facilitates a number of vital cellular functions coupled with their roles, which range from the intercellular propagation of electrical signals to the selective intercellular passage of small regulatory molecules. Importantly, the extent of gap-junctional intercellular communication is under the direct control of regulatory events associated with channel assembly and turnover, as the vast majority of connexins have remarkably short half-lives of only a few hours. Since most cell types express multiple members of the connexin family, compensatory mechanisms exist to salvage tissue function in cases when one connexin is mutated or lost. However, numerous studies of the last decade have revealed that mutations in connexin genes can also lead to severe and debilitating diseases. In many cases, single point mutations lead to dramatic effects on connexin trafficking, assembly and channel function. This review will assess the current understanding of wild-type and selected disease-linked mutant connexin transport through the secretory pathway, gap-junction assembly at the cell surface, internalization and degradation.
| S-EPMC1383703 | biostudies-other
Project description:In recent years, significant advances have been made in the study of lymphatic vessels with the identification of their specific markers and the development of research tools that have accelerated our understanding of their role in tissue homeostasis and disease pathogenesis in many organs. Compared to other organs, the lymphatic system in the liver is understudied despite its obvious importance for hepatic physiology and pathophysiology. In this review, we describe fundamental aspects of the hepatic lymphatic system and its role in a range of liver-related pathological conditions such as portal hypertension, ascites formation, malignant tumours, liver transplantation, congenital liver diseases, non-alcoholic fatty liver disease, and hepatic encephalopathy. The article concludes with a discussion regarding the modulation of lymphangiogenesis as a potential therapeutic strategy for liver diseases.
| S-EPMC9870070 | biostudies-literature
Project description:Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) form large-pore nonselective channels in the plasma membrane of cells and were suggested to play a role in the pathophysiology of cerebral ischemia. To directly test a potential contribution of pannexins in ischemia-related mechanisms, we performed experiments in Px1(-/-), Px2(-/-), and Px1(-/-)Px2(-/-) knockout mice. IL-1? release, channel function in astrocytes, and cortical spreading depolarization were not altered in Px1(-/-)Px2(-/-) mice, indicating that, in contrast to previous concepts, these processes occur normally in the absence of pannexin channels. However, ischemia-induced dye release from cortical neurons was lower, indicating that channel function in Px1(-/-)Px2(-/-) neurons was impaired. Furthermore, Px1(-/-)Px2(-/-) mice had a better functional outcome and smaller infarcts than wild-type mice when subjected to ischemic stroke. In conclusion, our data demonstrate that Px1 and Px2 underlie channel function in neurons and contribute to ischemic brain damage.
| S-EPMC3251101 | biostudies-literature
Project description:Pannexins are channel proteins important for the release of calcium and adenosine triphosphate, which are among other functions involved in early development. Here, the expression of pannexins was investigated in induced pluripotent stem cells derived from human cord blood endothelial cells (hCBiPS2), in hematopoietic stem cell-derived induced pluripotent stem cells (HSC_F1285_T-iPS2) and in human embryonic stem cells (HES-3). The expression of pannexin (Panx) 1-3 mRNAs was analyzed in all three undifferentiated stem cell lines. Stem cells then underwent undirected differentiation into embryoid bodies and were analyzed regarding expression of germ layer-specific genes.Panx1, Panx2, and Panx3 mRNAs were expressed in all undifferentiated stem cell lines investigated. In comparison, Panx1 showed the highest expression among all pannexins. The undirected differentiation resulted in a mixed germ layer genotype in all three stem cell lines. Whereas the expression of Panx1 was not affected by differentiation, the expression of Panx2 was slightly increased in differentiated hCBiPS2 cells, HSC_F1285_T-iPS2 as well as HES3 cells as compared to their undifferentiated counterparts. A slight increase of Panx3 expression was observed in differentiated hCBiPS2 cells only. In conclusion, pluripotent stem cells express all three pannexin genes.
| S-EPMC5778636 | biostudies-literature
Project description:Pannexins are a second family of gap-junction proteins in vertebrates, classified as pannexin-1, pannexin-2, and pannexin-3. Pannexin-1 is one of the candidates for channel-mediated ATP release into the extracellular space. In airway epithelia, ATP signaling modulates multiple cellular functions such as mucus/ion secretion and mucociliary clearance systems. However, the expression of pannexins in the upper airway has not been investigated. Nasal septal mucosae were collected from adult male Wistar rats aged 20-24 weeks. The expression of pannexin-1, pannexin-2, and pannexin-3 was examined by reverse transcription polymerase chain reaction (RT-PCR) and by whole-mount fluorescence immunohistochemistry. Transcripts for pannexin-1, pannexin-2, and pannexin-3 were detected in nasal septal mucosae of adult rats by RT-PCR. Distinct immunohistochemical fluorescence for pannexin-1 was observed in the epithelial layer, whereas there was no immunoreactivity for pannexin-2 or pannexin-3. This is the first article establishing the existence of pannexins (predominantly pannexin-1) in the upper airway, suggesting their possible participation in the physiological functions of ATP release and signaling in this tissue.
| S-EPMC3793114 | biostudies-literature
Project description:Key pointsLymphatic valve defects are one of the major causes of lymph transport dysfunction; however, there are no accessible methods for quantitatively assessing valve function. This report describes a novel technique for quantifying lymphatic valve back-leak. Postnatal endothelial-specific deletion of connexin 43 (Cx43) in connexin 37 null (Cx37-/- ) mice results in rapid regression of valve leaflets and severe valve dysfunction. This method can also be used for assessing the function of venous and lymphatic valves from various species, including humans.AbstractThe lymphatic system relies on robust, spontaneous contractions of collecting lymphatic vessels and one-way secondary lymphatic valves to efficiently move lymph forward. Secondary valves prevent reflux and allow for the generation of propulsive pressure during each contraction cycle. Lymphatic valve defects are one of the major causes of lymph transport dysfunction. Genetic mutations in multiple genes have been associated with the development of primary lymphoedema in humans; and many of the same mutations in mice result in valve defects that subsequently lead to chylous ascites or chylothorax. At present the only experimental technique for the quantitative assessment of lymphatic valve function utilizes the servo-null micropressure system, which is highly accurate and precise, but relatively inaccessible and difficult to use. We developed a novel, simplified alternative method for quantifying valve function and determining the degree of pressure back-leak through an intact valve in pressurized, single-valve segments of isolated lymphatic vessels. With this diameter-based method, the competence of each lymphatic valve is challenged over a physiological range of pressures (e.g. 0.5-10cmH2 O) and pressure back-leak is extrapolated from calibrated, pressure-driven changes in diameter upstream from the valve. Using mesenteric lymphatic vessels from C57BL/6J, Ub-CreERT2 ;Rasa1fx/fx , Foxc2Cre/+ , Lyve1-Cre;Cx43fx/fx , and Prox1-CreERT2 ;Cx43fx/fx ;Cx37-/- mice, we tested our method on lymphatic valves displaying a wide range of dysfunction, from fully competent to completely incompetent. Our results were validated by simultaneous direct measurement of pressure back-leak using a servo-null micropressure system. Our diameter-based technique can be used to quantify valve function in isolated lymphatic valves from a variety of species. This method also revealed that haplodeficiency in Foxc2 (Foxc2Cre/+ ) is not sufficient to cause significant valve dysfunction; however, postnatal endothelial-specific deletion of Cx43 in Cx37-/- mice results in rapid regression of valve leaflets and severe valve dysfunction.
| S-EPMC8170716 | biostudies-literature
Project description:The plasma membrane contributes to the formation of autophagosomes, the double-membrane vesicles that sequester cytosolic cargo and deliver it to lysosomes for degradation during autophagy. In this study, we have identified a regulatory role for connexins (Cx), the main components of plasma membrane gap junctions, in autophagosome formation. We have found that plasma-membrane-localized Cx proteins constitutively downregulate autophagy through a direct interaction with several autophagy-related proteins involved in the initial steps of autophagosome formation, such as Atg16 and components of the PI(3)K autophagy initiation complex (Vps34, Beclin-1 and Vps15). On nutrient starvation, this inhibitory effect is released by the arrival of Atg14 to the Cx-Atg complex. This promotes the internalization of Cx-Atg along with Atg9, which is also recruited to the plasma membrane in response to starvation. Maturation of the Cx-containing pre-autophagosomes into autophagosomes leads to degradation of these endogenous inhibitors, allowing for sustained activation of autophagy.
| S-EPMC4008708 | biostudies-literature