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1.
Invest Ophthalmol Vis Sci ; 60(12): 4021-4032, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31560767

RESUMO

Purpose: Connexins and aquaporins play essential roles in maintaining lens homeostasis and transparency and there is a close physical and functional relationship between these two proteins. Aquaporin 0 (AQP0), in addition to its role in water transport in the lens, acts as a cell-cell adhesion molecule. Recently, we showed a new role of connexin (Cx) 50 in mediating cell-cell adhesion. However, the cooperative roles of these two proteins in the lens in vivo have not been reported. Methods: We generated an AQP0/Cx50 double knockout (dKO) mouse model. Light, fluorescence, transmission thin section, and freeze-fracture electron microscopy, as well as wheat germ agglutinin and phalloidin labeling were used to evaluate lens structure. Mechanical properties of lenses were determined by mechanical compression testing. Results: DKO mice exhibited small eyes and lenses with severe cataracts, along with lens posterior defects, including posterior capsule rupture. The dKO mouse lenses had severe structural disruption associated with increased spaces between lens fiber cells when compared with wild-type lenses or lenses deficient in either Cx50 or AQP0. DKO mice also exhibited greater reduction in lens size compared with Cx50 KO mice. Gap-junction plaque size was greatly decreased in cortical fiber cells in dKO mice. Moreover, lens stiffness and elasticity were completely diminished, exhibiting a gelatinous texture in adult dKO mice. Conclusions: This novel mouse model reveals that Cx50 and AQP0 play an important role in mediating cell-cell adhesion function in the lens fiber cells and their deficiency impairs lens fiber organization, integrity, mechanical properties, and lens development.


Assuntos
Aquaporinas/fisiologia , Catarata/metabolismo , Conexinas/fisiologia , Anormalidades do Olho/metabolismo , Proteínas do Olho/fisiologia , Cristalino/metabolismo , Animais , Catarata/patologia , Adesão Celular/fisiologia , Anormalidades do Olho/patologia , Feminino , Técnica de Fratura por Congelamento , Cristalino/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Pupila/fisiologia
2.
Invest Ophthalmol Vis Sci ; 60(6): 2336-2346, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31117126

RESUMO

Purpose: Mutations in connexin50 (Cx50) and connexin46 (Cx46) cause cataracts. Because the expression of Cx46fs380 leads to decreased gap junctional coupling and formation of calcium precipitates, we studied Cx50D47A lenses to test whether Cx50 mutants also cause cataracts due to calcium precipitation. Methods: Connexin levels were determined by immunoblotting. Gap junctional coupling conductance was calculated from intracellular impedance studies of intact lenses. Intracellular hydrostatic pressure was measured using a microelectrode/manometer system. Intracellular free calcium ion concentrations ([Ca2+]i) were measured using Fura-2 and fluorescence imaging. Calcium precipitation was assessed by Alizarin red staining and compared to the distribution of opacities in darkfield images. Results: In Cx50D47A lenses, Cx50 levels were 11% (heterozygotes) and 1.2% (homozygotes), and Cx46 levels were 52% (heterozygotes) and 30% (homozygotes) when compared to wild-type at 2.5 months. Gap junctional coupling in differentiating fibers of Cx50D47A lenses was 49% (heterozygotes) and 29% (homozygotes), and in mature fibers, it was 24% (heterozygotes) and 4% (homozygotes) compared to wild-type lenses. Hydrostatic pressure was significantly increased in Cx50D47A lenses. [Ca2+]i was significantly increased in Cx50D47A lenses. Alizarin red-stained calcium precipitates were present in homozygous Cx50D47A lenses with a similar distribution to the cataracts. Conclusions: Cx50D47A expression altered the lens internal circulation by decreasing connexin levels and gap junctional coupling. Reduced water and ion outflow through gap junctions increased the gradients of intracellular hydrostatic pressure and concentrations of free calcium ions. In these lenses, calcium ions accumulated, precipitated, and formed cataracts. These results suggest that mutant lens fiber connexins lead to calcium precipitates, which may cause cataracts.


Assuntos
Cálcio/metabolismo , Catarata/metabolismo , Conexinas/fisiologia , Cristalino/metabolismo , Animais , Conexinas/metabolismo , Modelos Animais de Doenças , Junções Comunicantes/metabolismo , Camundongos
4.
EMBO J ; 38(10)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30902848

RESUMO

Pyroptosis is a form of lytic inflammatory cell death driven by inflammatory caspase-1, caspase-4, caspase-5 and caspase-11. These caspases cleave and activate the pore-forming protein gasdermin D (GSDMD) to induce membrane damage. By contrast, apoptosis is driven by apoptotic caspase-8 or caspase-9 and has traditionally been classified as an immunologically silent form of cell death. Emerging evidence suggests that therapeutics designed for cancer chemotherapy or inflammatory disorders such as SMAC mimetics, TAK1 inhibitors and BH3 mimetics promote caspase-8 or caspase-9-dependent inflammatory cell death and NLRP3 inflammasome activation. However, the mechanism by which caspase-8 or caspase-9 triggers cell lysis and NLRP3 activation is still undefined. Here, we demonstrate that during extrinsic apoptosis, caspase-1 and caspase-8 cleave GSDMD to promote lytic cell death. By engineering a novel Gsdmd D88A knock-in mouse, we further demonstrate that this proinflammatory function of caspase-8 is counteracted by caspase-3-dependent cleavage and inactivation of GSDMD at aspartate 88, and is essential to suppress GSDMD-dependent cell lysis during caspase-8-dependent apoptosis. Lastly, we provide evidence that channel-forming glycoprotein pannexin-1, but not GSDMD or GSDME promotes NLRP3 inflammasome activation during caspase-8 or caspase-9-dependent apoptosis.


Assuntos
Apoptose/fisiologia , Conexinas/fisiologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Células 3T3 , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Células Cultivadas , Embrião de Mamíferos , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Complexos Multiproteicos/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Ligação Proteica , Multimerização Proteica , Receptores Estrogênicos/metabolismo , Transdução de Sinais/fisiologia
5.
Ann N Y Acad Sci ; 1442(1): 79-90, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29952014

RESUMO

The pannexin 1 (Panx1) channel is a mechanosensitive channel that interacts with P2X7 receptors (P2X7R) to form a functional complex that has been shown in vitro to play an essential role in osteocyte mechanosignaling. While the participation of P2X7R in skeletal responses to mechanical loading has been demonstrated, the role of Panx1 and its interplay with P2X7R still remain to be determined. In this study, we use a global Panx1-/- mouse model and in vivo mechanical loading to demonstrate that Panx1 channels play an essential role in load-induced skeletal responses. We found that absence of Panx1 not only disrupts the P2X7R-Panx1 signaling complex, but also alters load-induced regulation of P2X7R expression. Moreover, lack of Panx1 completely abolished load-induced periosteal bone formation. Load-induced regulation of ß-catenin and sclerostin expression was dysregulated in Panx1-/- , compared to wild-type, bone. This finding suggests that Panx1 deficiency disrupts Wnt/ß-catenin signaling by lowering ß-catenin while favoring inhibition of bone formation by increasing load-induced sclerostin expression. This study demonstrates the existence of a Panx1-dependent mechanosensitive mechanism that not only modulates ATP signaling but also coordinates Wnt/ß-catenin signaling that is essential for proper skeletal response to mechanical loading.


Assuntos
Osso e Ossos/fisiologia , Conexinas/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Estresse Mecânico , Animais , Desenvolvimento Ósseo , Conexinas/genética , Conexinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
6.
Neurosci Lett ; 695: 32-39, 2019 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28495272

RESUMO

In mammals, the pannexin gene family consists of three members (Panx1, 2, 3), which represent a class of integral membrane channel proteins sharing some structural features with chordate gap junction proteins, the connexins. Since their discovery in the early 21st century, pannexin expression has been detected throughout the vertebrate body including eye, ear, nose and tongue, making the investigation of the roles of this new class of channel protein in health and disease very appealing. The localization in sensory organs, coupled with unique channel properties and associations with major signaling pathways make Panx1, and its relative's, significant contributors for fundamental functions in sensory perception. Until recently, cell-based studies were at the forefront of pannexin research. Lately, the availability of mice with genetic ablation of pannexins opened new avenues for testing pannexin functions and behavioural phenotyping. Although we are only at the beginning of understanding the roles of pannexins in health and disease, this review summarizes recent advances in elucidating the various emerging roles pannexins play in sensory systems, with an emphasis on unresolved conflicts.


Assuntos
Conexinas/fisiologia , Audição/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Olfato/fisiologia , Paladar/fisiologia , Visão Ocular/fisiologia , Animais , Conexinas/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo
8.
Neurosci Lett ; 695: 53-64, 2019 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28911821

RESUMO

Electrical synapses with diverse configurations and functions occur at a variety of interneuronal appositions, thereby significantly expanding the physiological complexity of neuronal circuitry over that provided solely by chemical synapses. Gap junctions between apposed dendritic and somatic plasma membranes form "purely electrical" synapses that allow for electrical communication between coupled neurons. In addition, gap junctions at axon terminals synapsing on dendrites and somata allow for "mixed" (dual chemical+electrical) synaptic transmission. "Dual transmission" was first documented in the autonomic nervous system of birds, followed by its detection in the central nervous systems of fish, amphibia, and reptiles. Subsequently, mixed synapses have been detected in several locations in the mammalian CNS, where their properties and functional roles remain undetermined. Here, we review available evidence for the presence, complex structural composition, and emerging functional properties of mixed synapses in the mammalian CNS.


Assuntos
Sinapses Elétricas/fisiologia , Junções Comunicantes/fisiologia , Mamíferos/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Sistema Nervoso Central/metabolismo , Conexinas/fisiologia , Neurônios/fisiologia
9.
Neurosci Lett ; 695: 25-31, 2019 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28284836

RESUMO

It is the current view that purinergic signaling regulates many physiological functions. Pannexin1 (Panx1), a member of the gap junction family of proteins is an ATP releasing channel that plays important physio-pathological roles in various tissues, including the CNS. Upon binding to purinergic receptors expressed in neural cells, ATP triggers cellular responses including increased cell proliferation, cell morphology changes, release of cytokines, and regulation of neuronal excitability via release of glutamate, GABA and ATP itself. Under pathological conditions such as ischemia, trauma, inflammation, and epilepsy, extracellular ATP concentrations increases drastically but the consequences of this surge is still difficult to characterize due to its rapid metabolism in ADP and adenosine, the latter having inhibitory action on neuronal activity. For seizures, for instance, the excitatory effect of ATP on neuronal activity is mainly related to its action of P2X receptors, while the inhibitory effects are related to activation of P1, adenosine receptors. Here we provide a mini review on the properties of pannexins with a main focus on Panx1 and its involvement in seizure activity. Although there are only few studies implicating Panx1 in seizures, they are illustrative of the dual role that Panx1 has on neuronal excitability.


Assuntos
Conexinas/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Conexinas/química , Conexinas/genética , Conexinas/metabolismo , Junções Comunicantes/metabolismo , Junções Comunicantes/fisiologia , Humanos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , Transdução de Sinais
10.
J Gen Physiol ; 150(12): 1758-1768, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30377218

RESUMO

Pannexins are a family of ATP release channels important for physiological and pathological processes like blood pressure regulation, epilepsy, and neuropathic pain. To study these important channels in vitro, voltage stimulation is the most common and convenient tool, particularly for pannexin 1 (Panx1). However, whether Panx1 is a voltage-gated channel remains controversial. Here, we carefully examine the effect of N-terminal modification on voltage-dependent Panx1 channel activity. Using a whole-cell patch-clamp recording technique, we demonstrate that both human and mouse Panx1, with their nativeN termini, give rise to voltage-dependent currents, but only at membrane potentials larger than +100 mV. This weak voltage-dependent channel activity profoundly increases when a glycine-serine (GS) motif is inserted immediately after the first methionine. Single-channel recordings reveal that the addition of GS increases the channel open probability as well as the number of unitary conductance classes. We also find that insertions of other amino acid(s) at the same position mimics the effect of GS. On the other hand, tagging the N terminus with GFP abolishes voltage-dependent channel activity. Our results suggest that Panx1 is a channel with weak voltage dependence whose activity can be tuned by N-terminal modifications.


Assuntos
Conexinas/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Animais , Células CHO , Cricetulus , Células HEK293 , Humanos , Potenciais da Membrana , Mutagênese Insercional , Técnicas de Patch-Clamp
11.
J Gen Physiol ; 150(12): 1606-1639, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30389716

RESUMO

As the physiology of synapses began to be explored in the 1950s, it became clear that electrical communication between neurons could not always be explained by chemical transmission. Instead, careful studies pointed to a direct intercellular pathway of current flow and to the anatomical structure that was (eventually) called the gap junction. The mechanism of intercellular current flow was simple compared with chemical transmission, but the consequences of electrical signaling in excitable tissues were not. With the recognition that channels were a means of passive ion movement across membranes, the character and behavior of gap junction channels came under scrutiny. It became evident that these gated channels mediated intercellular transfer of small molecules as well as atomic ions, thereby mediating chemical, as well as electrical, signaling. Members of the responsible protein family in vertebrates-connexins-were cloned and their channels studied by many of the increasingly biophysical techniques that were being applied to other channels. As described here, much of the evolution of the field, from electrical coupling to channel structure-function, has appeared in the pages of the Journal of General Physiology.


Assuntos
Conexinas/fisiologia , Eletrofisiologia/história , Junções Comunicantes/fisiologia , Potenciais de Ação , Animais , História do Século XX , História do Século XXI , Humanos , Sinapses/fisiologia
12.
Sci Adv ; 4(8): eaas9846, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30101191

RESUMO

Chronic joint pain such as mechanical allodynia is the most debilitating symptom of arthritis, yet effective therapies are lacking. We identify the pannexin-1 (Panx1) channel as a therapeutic target for alleviating mechanical allodynia, a cardinal sign of arthritis. In rats, joint pain caused by intra-articular injection of monosodium iodoacetate (MIA) was associated with spinal adenosine 5'-triphosphate (ATP) release and a microglia-specific up-regulation of P2X7 receptors (P2X7Rs). Blockade of P2X7R or ablation of spinal microglia prevented and reversed mechanical allodynia. P2X7Rs drive Panx1 channel activation, and in rats with mechanical allodynia, Panx1 function was increased in spinal microglia. Specifically, microglial Panx1-mediated release of the proinflammatory cytokine interleukin-1ß (IL-1ß) induced mechanical allodynia in the MIA-injected hindlimb. Intrathecal administration of the Panx1-blocking peptide 10panx suppressed the aberrant discharge of spinal laminae I-II neurons evoked by innocuous mechanical hindpaw stimulation in arthritic rats. Furthermore, mice with a microglia-specific genetic deletion of Panx1 were protected from developing mechanical allodynia. Treatment with probenecid, a clinically used broad-spectrum Panx1 blocker, resulted in a striking attenuation of MIA-induced mechanical allodynia and normalized responses in the dynamic weight-bearing test, without affecting acute nociception. Probenecid reversal of mechanical allodynia was also observed in rats 13 weeks after anterior cruciate ligament transection, a model of posttraumatic osteoarthritis. Thus, Panx1-targeted therapy is a new mechanistic approach for alleviating joint pain.


Assuntos
Artralgia/prevenção & controle , Artrite Experimental/prevenção & controle , Conexinas/metabolismo , Conexinas/fisiologia , Hiperalgesia/prevenção & controle , Microglia/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Doenças da Medula Espinal/prevenção & controle , Animais , Artralgia/etiologia , Artrite Experimental/etiologia , Conexinas/genética , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Ratos , Ratos Sprague-Dawley , Doenças da Medula Espinal/etiologia
13.
PLoS Genet ; 14(8): e1007488, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30071018

RESUMO

Women and other mammalian females are born with a finite supply of oocytes that determine their reproductive lifespan. During fetal development, individual oocytes are enclosed by a protective layer of granulosa cells to form primordial follicles that will grow, mature, and eventually release the oocyte for potential fertilization. Despite the knowledge that follicles are dysfunctional and will die without granulosa cell-oocyte interactions, the mechanisms by which these cells establish communication is unknown. We previously identified that two members of the Iroquois homeobox transcription factor gene family, Irx3 and Irx5, are expressed within developing ovaries but not testes. Deletion of both factors (Irx3-Irx5EGFP/Irx3-Irx5EGFP) disrupted granulosa cell-oocyte contact during early follicle development leading to oocyte death. Thus, we hypothesized that Irx3 and Irx5 are required to develop cell-cell communication networks to maintain follicle integrity and female fertility. A series of Irx3 and Irx5 mutant mouse models were generated to assess roles for each factor. While both Irx3 and Irx5 single mutant females were subfertile, their breeding outcomes and ovary histology indicated distinct causes. Careful analysis of Irx3- and Irx5-reporter mice linked the cause of this disparity to dynamic spatio-temporal changes in their expression patterns. Both factors marked the progenitor pre-granulosa cell population in fetal ovaries. At the critical phase of germline nest breakdown and primordial follicle formation however, Irx3 and Irx5 transitioned to oocyte- and granulosa cell-specific expression respectively. Further investigation into the cause of follicle death in Irx3-Irx5EGFP/Irx3-Irx5EGFP ovaries uncovered specific defects in both granulosa cells and oocytes. Granulosa cell defects included poor contributions to basement membrane deposition and mis-localization of gap junction proteins. Granulosa cells and oocytes both presented fewer cell projections resulting in compromised cell-cell communication. Altogether, we conclude that Irx3 and Irx5 first work together to define the pregranulosa cell population of germline nests. During primordial follicle formation, they transition to oocyte- and granulosa cell-specific expression patterns where they cooperate in neighboring cells to build the foundation for follicle integrity. This foundation is left as their legacy of the essential oocyte-granulosa cell communication network that ensures and ultimately optimizes the integrity of the ovarian reserve and therefore, the female reproductive lifespan.


Assuntos
Células da Granulosa/fisiologia , Proteínas de Homeodomínio/fisiologia , Fatores de Transcrição/fisiologia , Animais , Comunicação Celular , Conexinas/genética , Conexinas/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células Germinativas , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Nus , Oócitos/fisiologia , Fatores de Transcrição/genética
14.
Reprod Toxicol ; 81: 207-219, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30130578

RESUMO

Epididymal sperm maturation is a critical aspect of male reproduction in which sperm acquire motility and the ability to fertilize an ovum. Sperm maturation is dependent on the creation of a specific environment that changes along the epididymis and which enables the maturation process. The blood-epididymis barrier creates a unique luminal micro-environment, different from blood, by limiting paracellular transport and forcing receptor-mediated transport of macromolecules across the epididymal epithelium. Direct cellular communication between cells allows coordinated function of the epithelium. A limited number of studies have directly examined the effects of toxicants on junctional proteins and barrier function in the epididymis. Effects on the integrity of the blood-epididymis barrier have resulted in decreased fertility and, in some cases, the development of sperm granulomas. Studies have shown that in addition to tight junctions, proteins implicated in the maintenance of adherens junctions and gap junctions alter epididymal functions. This review will provide an overview of the types and roles of cellular junctions in the epididymis, and how these are targeted by different toxicants.


Assuntos
Epididimo/fisiologia , Junções Intercelulares/fisiologia , Reprodução/fisiologia , Animais , Conexinas/fisiologia , Humanos , Masculino
15.
J Neurosci ; 38(35): 7713-7724, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30037834

RESUMO

CSF-contacting (CSF-c) cells are present in the walls of the brain ventricles and the central canal of the spinal cord and found throughout the vertebrate phylum. We recently identified ciliated somatostatin-/GABA-expressing CSF-c neurons in the lamprey spinal cord that act as pH sensors as well as mechanoreceptors. In the same neuron, acidic and alkaline responses are mediated through ASIC3-like and PKD2L1 channels, respectively. Here, we investigate the functional properties of the ciliated somatostatin-/GABA-positive CSF-c neurons in the hypothalamus by performing whole-cell recordings in hypothalamic slices. Depolarizing current pulses readily evoked action potentials, but hypothalamic CSF-c neurons had no or a very low level of spontaneous activity at pH 7.4. They responded, however, with membrane potential depolarization and trains of action potentials to small deviations in pH in both the acidic and alkaline direction. Like in spinal CSF-c neurons, the acidic response in hypothalamic cells is mediated via ASIC3-like channels. In contrast, the alkaline response appears to depend on connexin hemichannels, not on PKD2L1 channels. We also show that hypothalamic CSF-c neurons respond to mechanical stimulation induced by fluid movements along the wall of the third ventricle, a response mediated via ASIC3-like channels. The hypothalamic CSF-c neurons extend their processes dorsally, ventrally, and laterally, but as yet, the effects exerted on hypothalamic circuits are unknown. With similar neurons being present in rodents, the pH- and mechanosensing ability of hypothalamic CSF-c neurons is most likely conserved throughout vertebrate phylogeny.SIGNIFICANCE STATEMENT CSF-contacting neurons are present in all vertebrates and are located mainly in the hypothalamic area and the spinal cord. Here, we report that the somatostatin-/GABA-expressing CSF-c neurons in the lamprey hypothalamus sense bidirectional deviations in the extracellular pH and do so via different molecular mechanisms. They also serve as mechanoreceptors. The hypothalamic CSF-c neurons have extensive axonal ramifications and may decrease the level of motor activity via release of somatostatin. In conclusion, hypothalamic somatostatin-/GABA-expressing CSF-c neurons, as well as their spinal counterpart, represent a novel homeostatic mechanism designed to sense any deviation from physiological pH and thus constitute a feedback regulatory system intrinsic to the CNS, possibly serving a protective role from damage caused by changes in pH.


Assuntos
Canais Iônicos Sensíveis a Ácido/fisiologia , Líquido Cefalorraquidiano/fisiologia , Concentração de Íons de Hidrogênio , Hipotálamo/citologia , Mecanorreceptores/fisiologia , Neurônios/fisiologia , Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Potenciais de Ação , Animais , Conexinas/antagonistas & inibidores , Conexinas/fisiologia , Feminino , Junções Comunicantes/fisiologia , Lampreias , Masculino , Movimento (Física) , Técnicas de Patch-Clamp , Estimulação Física , Somatostatina/análise , Estresse Mecânico , Terceiro Ventrículo , Ácido gama-Aminobutírico/análise
17.
Annu Rev Vis Sci ; 4: 79-100, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29889655

RESUMO

Electrical synaptic transmission via gap junctions underlies direct and rapid neuronal communication in the central nervous system. The diversity of functional roles played by electrical synapses is perhaps best exemplified in the vertebrate retina, in which gap junctions are expressed by each of the five major neuronal types. These junctions are highly plastic; they are dynamically regulated by ambient illumination and circadian rhythms acting through light-activated neuromodulators. The networks formed by electrically coupled neurons provide plastic, reconfigurable circuits positioned to play key and diverse roles in the transmission and processing of visual information at every retinal level. Recent work indicates gap junctions also play a role in the progressive cell death and aberrant activity seen in various pathological conditions of the retina. Gap junctions thus form potential targets for novel neuroprotective therapies in the treatment of neurodegenerative retinal diseases such as glaucoma and ischemic retinopathies.


Assuntos
Sinapses Elétricas/fisiologia , Junções Comunicantes/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Retina/fisiologia , Transmissão Sináptica/fisiologia , Animais , Comunicação Celular/fisiologia , Sistema Nervoso Central/fisiologia , Conexinas/fisiologia , Humanos
18.
Int J Mol Sci ; 19(6)2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29865195

RESUMO

Since their characterization more than five decades ago, gap junctions and their structural proteins-the connexins-have been associated with cancer cell growth. During that period, the accumulation of data and molecular knowledge about this association revealed an apparent contradictory relationship between them and cancer. It appeared that if gap junctions or connexins can down regulate cancer cell growth they can be also implied in the migration, invasion and metastatic dissemination of cancer cells. Interestingly, in all these situations, connexins seem to be involved through various mechanisms in which they can act either as gap-junctional intercellular communication mediators, modulators of signalling pathways through their interactome, or as hemichannels, which mediate autocrine/paracrine communication. This complex involvement of connexins in cancer progression is even more complicated by the fact that their hemichannel function may overlap with other gap junction-related proteins, the pannexins. Despite this complexity, the possible involvements of connexins and pannexins in cancer progression and the elucidation of the mechanisms they control may lead to use them as new targets to control cancer progression. In this review, the involvements of connexins and pannexins in these different topics (cancer cell growth, invasion/metastasis process, possible cancer therapeutic targets) are discussed.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese , Conexinas/metabolismo , Metástase Neoplásica , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Comunicação Celular , Conexinas/antagonistas & inibidores , Conexinas/fisiologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transdução de Sinais
19.
Eur Arch Otorhinolaryngol ; 275(6): 1657-1661, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29574598

RESUMO

BACKGROUND: Nasal mucosal epithelial cells express connexins, the prototypical gap junction proteins, and pannexins, a new family of channel proteins homologous to the invertebrate gap junction proteins. The physiological and pathophysiological roles of these transmembrane proteins in nasal mucosa are largely still unknown. PURPOSE: Pannexins participate in ATP release into the extracellular space in various tissues, and ATP plays important roles in mucociliary clearance, especially by regulating ciliary beat activity. Therefore, we focused on the functional relationship between connexins, pannexin-1, ATP release, and mucociliary clearance in nasal epithelia. RESULTS AND CONCLUSIONS: Connexins participate in the generation of intercellular calcium waves, in which calcium-mediated signaling responses spread to contiguous cells through the gap junction formed by connexins to transmit calcium signaling throughout the airway epithelium. Pannexins in the nasal mucosa may contribute to not only ciliary beat modulation via ATP release, but also regulation of mucus blanket components via H2O efflux. The synchronized roles of pannexin and connexin may provide a new insight into effective mucociliary clearance systems in nasal mucosa.


Assuntos
Conexinas/fisiologia , Células Epiteliais/metabolismo , Mucosa Nasal/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Animais , Junções Comunicantes , Depuração Mucociliar/fisiologia
20.
Nat Rev Rheumatol ; 14(1): 42-51, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29255213

RESUMO

Connexons form the basis of hemichannels and gap junctions. They are composed of six tetraspan proteins called connexins. Connexons can function as individual hemichannels, releasing cytosolic factors (such as ATP) into the pericellular environment. Alternatively, two hemichannel connexons from neighbouring cells can come together to form gap junctions, membrane-spanning channels that facilitate cell-cell communication by enabling signalling molecules of approximately 1 kDa to pass from one cell to an adjacent cell. Connexins are expressed in joint tissues including bone, cartilage, skeletal muscle and the synovium. Indicative of their importance as gap junction components, connexins are also known as gap junction proteins, but individual connexin proteins are gaining recognition for their channel-independent roles, which include scaffolding and signalling functions. Considerable evidence indicates that connexons contribute to the function of bone and muscle, but less is known about the function of connexons in other joint tissues. However, the implication that connexins and gap junctional channels might be involved in joint disease, including age-related bone loss, osteoarthritis and rheumatoid arthritis, emphasizes the need for further research into these areas and highlights the therapeutic potential of connexins.


Assuntos
Conexina 43/metabolismo , Conexinas/metabolismo , Junções Comunicantes/metabolismo , Artropatias/metabolismo , Animais , Artrite Reumatoide/metabolismo , Osso e Ossos/metabolismo , Cartilagem/metabolismo , Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Conexinas/fisiologia , Conexinas/uso terapêutico , Junções Comunicantes/fisiologia , Humanos , Ativação do Canal Iônico/fisiologia , Canais Iônicos/fisiologia , Camundongos , Camundongos Knockout , Sistema Musculoesquelético/metabolismo , Sistema Musculoesquelético/patologia , Osteoartrite/metabolismo , Osteoporose/metabolismo , Membrana Sinovial/metabolismo
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