Is the Exposome Involved in Brain Disorders through the Serotoninergic System?

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine acting as a neurotransmitter in the central nervous system (CNS), local mediator in the gut, and vasoactive agent in the blood. It has been linked to a variety of CNS functions and is implicated in many CNS and psychiatric disorders. The high comorbidity between some neuropathies can be partially understood by the fact that these diseases share a common etiology involving the serotoninergic system.

Brain Disorders and Chemical Pollutants: A Gap Junction Link?

The incidence of brain pathologies has increased during last decades. Better diagnosis (autism spectrum disorders) and longer life expectancy (Parkinson's disease, Alzheimer's disease) partly explain this increase, while emerging data suggest pollutant exposures as a possible but still underestimated cause of major brain disorders. Taking into account that the brain parenchyma is rich in gap junctions and that most pollutants inhibit their function; brain disorders might be the consequence of gap-junctional alterations due to long-term exposures to pollutants.

Serotonin and human cancer: A critical view.

Besides its classical functions as a neurotransmitter in the central nervous system, local mediator in the gastrointestinal tract and vasoactive agent in the blood, serotonin has more recently emerged as a growth factor for human tumor cells of different origins (carcinomas, glioma and carcinoids). Several data are also available on serotonin involvement in cancer cell migration, metastatic dissemination and tumor angiogenesis. The serotonin-induced signaling pathways that promote tumor progression are complex and only partly understood in some cancer types.

Targeting Gap Junctions: New Insights into the Treatment of Major Depressive Disorder.

Background: Major depressive disorder (MDD) is a multifactorial chronic and debilitating mood disease with high lifetime prevalence and associated with excess mortality. Treatments for this disease are not effective in all patients showing the need to find new therapeutic targets.

Objective: This review aims to update our knowledge on the involvement of astroglial gap junctions and hemichannels in MDD and to show how they have become potential targets for the treatment of this pathology.

Connexin43- and Pannexin-Based Channels in Neuroinflammation and Cerebral Neuropathies.

Connexins (Cx) are largely represented in the central nervous system (CNS) with 11 Cx isoforms forming intercellular channels. Moreover, in the CNS, Cx43 can form hemichannels (HCs) at non-junctional membrane as does the related channel-forming Pannexin1 (Panx1) and Panx2. Opening of Panx1 channels and Cx43 HCs appears to be involved in inflammation and has been documented in various CNS pathologies.

Involvement of gap junction channels in the pathophysiology of migraine with aura.

Migraine is a common, recurrent, and disabling primary headache disorder with a genetic component which affects up to 20% of the population. One third of all patients with migraine experiences aura, a focal neurological disturbance that manifests itself as visual, sensitive or motor symptoms preceding the headache. In the pathophysiology of migraine with aura, activation of the trigeminovascular system from the meningeal vessels mediates migraine pain via the brainstem and projections ascend to the thalamus and cortex.

Influence of the scaffolding protein Zonula Occludens (ZOs) on membrane channels.

Zonula Occludens (ZO) proteins are ubiquitous scaffolding proteins providing the structural basis for the assembly of multiprotein complexes at the cytoplasmic surface of the plasma membrane and linking transmembrane proteins to the filamentous cytoskeleton. They belong to the large family of membrane-associated guanylate kinase (MAGUK)-like proteins comprising a number of subfamilies based on domain content and sequence similarity. ZO proteins were originally described to localize specifically to tight junctions, or Zonulae Occludentes, but this notion was rapidly reconsidered since ZO proteins were found to associate with adherens junctions as well as with gap junctions, particularly with connexin-made intercellular channels, and also with a few other membrane channels.

Gap junctional channels are parts of multiprotein complexes.

Gap junctional channels are a class of membrane channels composed of transmembrane channel-forming integral membrane proteins termed connexins, innexins or pannexins that mediate direct cell-to-cell or cell-to extracellular medium communication in almost all animal tissues. The activity of these channels is tightly regulated, particularly by intramolecular modifications as phosphorylations of proteins and via the formation of multiprotein complexes where pore-forming subunits bind to auxiliary channel subunits and associate with scaffolding proteins that play essential roles in channel localization and activity. Scaffolding proteins link signaling enzymes, substrates, and potential effectors (such as channels) into multiprotein signaling complexes that may be anchored to the cytoskeleton.

5-HT4 and 5-HT2 receptors antagonistically influence gap junctional coupling between rat auricular myocytes.

5-hydroxytryptamine-4 (5-HT(4)) receptors have been proposed to contribute to the generation of atrial fibrillation in human atrial myocytes, but it is unclear if these receptors are present in the hearts of small laboratory animals (e.g. rat).

Reciprocal influence of connexins and apical junction proteins on their expressions and functions.

Membranes of adjacent cells form intercellular junctional complexes to mechanically anchor neighbour cells (anchoring junctions), to seal the paracellular space and to prevent diffusion of integral proteins within the plasma membrane (tight junctions) and to allow cell-to-cell diffusion of small ions and molecules (gap junctions). These different types of specialised plasma membrane microdomains, sharing common adaptor molecules, particularly zonula occludens proteins, frequently present intermingled relationships where the different proteins co-assemble into macromolecular complexes and their expressions are co-ordinately regulated. Proteins forming gap junction channels (connexins, particularly) and proteins fulfilling cell attachment or forming tight junction strands mutually influence expression and functions of one another.

RhoA GTPase and F-actin dynamically regulate the permeability of Cx43-made channels in rat cardiac myocytes.

Gap junctions are clusters of transmembrane channels allowing a passive diffusion of ions and small molecules between adjacent cells. Connexin43, the main channel-forming protein expressed in ventricular myocytes, can associate with zonula occludens-1, a scaffolding protein linked to the actin cytoskeleton and to signal transduction molecules. The possible influence of Rho GTPases, major regulators of cellular junctions and of the actin cytoskeleton, in the modulation of gap junctional intercellular communication (GJIC) was examined.

The connexin turnover, an important modulating factor of the level of cell-to-cell junctional communication: comparison with other integral membrane proteins.

The constituent proteins of gap junctions, called "connexins" (Cxs) in chordates, are generally renewed several times a day, in approximately the same rate range as many other integral plasma membrane proteins and the proteins of other channels, other intercellular junctions or different membrane receptors. This permanent renewal turns on a fine-tuned balance among various processes, such as gene transcription, mRNA stability and processing, protein synthesis and oligomerization, posttranslational modifications, transport to the plasma membrane, anchoring to the cytoskeleton, connexon aggregation and docking, regulation of endocytosis and controlled degradations of the proteins. Subtle changes at one or some of these steps would represent an exquisite level of regulation that extends beyond the rapid channel opening and closure events associated with channel gating; membrane channels and receptors are constantly able to answer to physiological requirements to either up- or downregulate their activity.

Gap junctional complexes: from partners to functions.

Gap junctions (GJ), specialised membrane structures that mediate cell-to-cell communication in almost all animal tissues, are composed of intercellular channel-forming integral membrane proteins termed connexins (Cxs), innexins or pannexins. The activity of these channels is closely regulated, particularly by intramolecular modifications as phosphorylation of proteins, via the formation of multiprotein complexes where pore-forming subunits bind to auxiliary channel subunits and associate with scaffolding proteins that play essential roles in channel localization and activity. Scaffolding proteins link signalling enzymes, substrates, and potential effectors (such as channels) into multiprotein signalling complexes that may be anchored to the cytoskeleton.

Protein phosphatase modulation of the intercellular junctional communication: importance in cardiac myocytes.

The rhythmic contraction of a four-chambered heart is a highly co-ordinated process, requiring the sequential activation of pacemaker cells and the propagation of activity throughout the whole myocardium. Gap-junctional channels, providing enclosed conduits for direct cell-to-cell transfer of ions and small molecules between adjacent cells, allow depolarising currents to flow from excited to non-excited regions of the network and a gradual spreading of the action potential. Gap-junctional channels are dodecamers of transmembrane proteins belonging in chordates to the connexin (Cx) family.

Diversity in protein-protein interactions of connexins: emerging roles.

Gap junctions, specialised membrane structures that mediate cell-to-cell communication in almost all tissues, are composed of channel-forming integral membrane proteins termed connexins. The activity of these intercellular channels is closely regulated, particularly by intramolecular modifications as phosphorylations of proteins by protein kinases, which appear to regulate the gap junction at several levels, including assembly of channels in the plasma membrane, connexin turnover as well as directly affecting the opening and closure ("gating") of channels. The regulation of membrane channels by protein phosphorylation/dephosphorylation processes commonly requires the formation of a multiprotein complex, where pore-forming subunits bind to auxiliary proteins (e.

Is the junctional uncoupling elicited in rat ventricular myocytes by some dephosphorylation treatments due to changes in the phosphorylation status of Cx43?

Gap junctions, specialized membrane structures that mediate cell-to-cell communication in almost all animal tissues, are composed of channel-forming integral membrane proteins termed connexins. Most of them, particularly connexin43 (Cx43), the most ubiquitous connexin, the major connexin present in cardiac myocytes, are phosphoproteins. Connexin phosphorylation has been thought to regulate gap junctional protein trafficking, gap junction assembly, channel gating, and turnover.

The metabolic inhibitor antimycin A can disrupt cell-to-cell communication by an ATP- and Ca(2+)-independent mechanism.

In cardiac myocytes of new-born rats, the degree of intercellular communication through gap junctional channels closely depends on the metabolic state of the cells. In contrast, in stably transfected HeLa cells expressing rat cardiac connexin43 (Cx43, the main channel-forming protein present in ventricular myocytes), a major part of junctional communication persisted in ATP-depleted conditions, in the presence of a metabolic inhibitor (KCN) or of a broad spectrum inhibitor of protein kinases (H7). However, another metabolic inhibitor, antimycin A, which like cyanide inhibits electron transfer in the respiratory chain, totally interrupted cell-to-cell communication between Cx43-HeLa cells, even in whole-cell conditions, when ATP (5 mM) was present.

Modulation of junctional communication by phosphorylation: protein phosphatases, the missing link in the chain.

Protein phosphorylation has been proposed to control the degree of intercellular gap junctional communication at several steps, from gene expression to protein degradation. In vertebrates, gap junctions are composed of proteins from the "connexin" (Cx) gene family, and the majority of connexins are post-translationally modified by phosphorylation. Alterations in the phosphorylation status of proteins, resulting from the dynamic interplay of protein kinases and protein phosphatases, are thought to be involved in a broad variety of connexin processes (such as the trafficking, assembly/disassembly and degradation, as well as the gating of gap junction channels), but the underlying mechanisms remain poorly understood.