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1st Edition

Clicking on the menu opens accessibility buttons. After choosing a subject in the menu, waiting time is necessary for the page to upload. They play important roles in different biological processes. These include differentiation, cell cycle synchronization, cellular development, neuronal activity and the immune response 5,7,9.

Several consensus cysteine residues in the extracellular loop are essential and necessary for intercellular docking of gap junction hemichannels in the opposing cell membrane 3,10, Connexins Cx include 21 integral membrane proteins belonging to this family and form homomeric or heteromeric hexamers generally termed connexons or hemi-channels. In turn, these hemi-channels further assemble in a head-to-head manner, thus forming gap junction channels 4,7.

Due to their important roles, mutations in connexins are linked to a number of diseases such as neurodegenerative disorders, skin diseases and developmental abnormalities 5,7, Pannexins Pannexin 1, Pannexin 2 and Pannexin 3 also belong to the superfamily of gap junction proteins. Not surprising, PANX1 gating properties depend whether it forms homomeric or heteromeric hemichannels.

Possible roles for Pannexins include paracrine signaling in vascular endothelial cells and taste cell signaling 6. Gap junctions are usually found in clusters and enable intercellular communication by allowing the passage of small molecules between cells 2. Proteins involved in gap junction formation are composed of four transmembrane domains, two extracellular loops and one intracellular loop and intracellular N- and C-termini 10, Connexins are ubiquitously expressed and their activity is regulated at the expression level and by post-translational modifications 4.

Gap junction

They can be used in a number of applications such as western blot analysis and immunocytochemistry. Spray and Burt 76 have proposed that low-pH induced uncoupling follows protonation of H residues.

An important role in determining the CO 2 sensitivity of Cx43 has been attributed to H95 77 , a residue located at the N-terminus of IL in most connexins. Both Cx32 and Cx38 have an H residue at that location, but their neighboring residues are different and this could account for their difference in pH sensitivity. However, in view of our data on the relevance of IL 2 74 , this residue may not play a key role in determining the CO 2 sensitivity of Cx32 and Cx More relevant to channel gating could be some of the H residues of IL 2. Recently, Hermans et al.

Although in preliminary experiments the replacement of H with R did not affect the CO 2 sensitivity of Cx32 75 , a more detailed evaluation of the potential role of these two residues is presently underway in our laboratory. Since CT chimeras did not express functional channels, the potential role of CT could not be tested with chimeras, but interesting data were obtained with mutations of basic residues at its initial residue segment C 1 and with CT deletions.

This is suggested by our recent data with mutants in which some or all of the positively charged residues R of C 1 were replaced with neutral polar residues N or T Interestingly, the 5 R residues were not all equally effective in inhibiting the Cx32 sensitivity to CO 2. R has greater inhibitory power than R, whereas R seems to partly counteract the inhibitory activity of both R and R A possible interpretation of these data is that the gating mechanism involves electrostatic interactions among intracellular domains of Cx IL 2 and C 1 are positively charged domains in all connexins, whereas IL 1 is the only cytoplasmic domain that is rich in negative charges.

Although IL 1 contains positive charges as well, being the most heavily charged domain of connexins, in a -helical conformation it would have positive and negative charges partitioned on opposite sides of the helix Figure 8 ; indeed, IL 1 , IL 2 and C 1 of Cx32 are likely to be a -helical and IL may have a helix-loop-helix structure, in view of the presence of G residues and and P residue residues at its mid-region.

As a working model, we are considering the possibility that in Cx32 under normal coupling conditions the negative charges of IL 1 are masked or somehow unavailable for electrostatic interaction with other domains. With CO 2 , conformational changes, brought about by changes in the connexin phosphorylation state, protonation of H residues, CaM binding, a combination of the above, or other as yet unknown factors, may expose them, allowing IL 2 and C 1 to competitively interact with IL 1.

IL 1 -IL 2 interaction would result in a closed channel state, whereas IL 1 -C 1 interaction would maintain the channel in an open state Figure 8. Based on this hypothesis, uncoupling efficiency would depend on differences between IL 2 and C 1 in binding affinity to IL 1.

In Cx32, one would predict C 1 to be a strong competitor of IL 2 , whereas the opposite would be true for connexins more sensitive to CO 2 , such as Cx38, Cx50, Cx45, etc. The gradual increase in Cx32 sensitivity to CO 2 that follows the progressive removal of positive charges in C 1 would be the consequence of a gradual decrease in the capacity of C 1 and IL 1 to interact with each other.

Although one should be well aware that based on the very limited amount of data this and any other potential model should not be valued more than working hypotheses, we feel that the potential participation of electrostatic interactions among connexin domains in the gating mechanism is worth careful study. A puzzling question is the apparent contradiction between our data on Cx32 and those of Delmar's group 40,70,71 on Cx43 regarding the relevance of CT in CO 2 gating.

Whereas we found most of the CT of Cx32 to be irrelevant and its initial regions C 1 to act as a gating inhibitor, Delmar's group found middle residues and end residues regions of the CT of Cx43 to be gating mediators or activators ; indeed, they have named the end of CT "the gating particle" of the ball-and-chain model Of course, it is quite possible that connexins are gated by different molecular mechanisms.

On the other hand, we think that there might be a common denominator for Cx32 and Cx43 data. A possibility is that in Cx43 the negatively charged region of the "gating particle" interacts with C 1 a basic-amphiphilic domain, as in Cx By doing so, the" gating particle" would eliminate the inhibitory function of C 1 , as it would prevent it from interacting with IL 1 ; its deletion would reduce CO 2 sensitivity because C 1 would then be free to bind to IL 1 and to act as inhibitor domain by competing against IL 2.

Indeed, acidic residues of the "gating particle" were found to be crucial for its function The proline-glycine-rich mid-region of CT may provide the hinge that enables the "gating particle" to bend backward and bind to C 1. Based on this interpretation, the reason why coexpressing Cx32 with the "gating particle" of Cx43 increases the CO 2 sensitivity of Cx32 70,71 would be that the "gating particle" of Cx43 interacts electrostatically with C 1 of Cx32 and blocks its inhibitory function.

Note that in Cx32 the end of the CT chain does not contain sequences even remotely similar to that of the "gating particle". This indicates that IL 2 plays an important role in pH gating sensitivity.

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Coupling between cells expressing different connexins has been demonstrated in many systems 1 , indicating that a cell-cell channel can be homotypic made of two connexons expressing the same connexin, Figure 9 a or heterotypic made of two connexons each expressing a different connexin, Figure 9 b 1.

In turn, connexons can be homomeric made of the same connexin, Figure 9 a and b or heteromeric composed of different connexins, Figure 9 c and d Therefore, cell-cell channels can be homomeric-homotypic Figure 9 a , homomeric-heterotypic Figure 9 b , monoheteromeric one connexon heteromeric and the other homomeric, Figure 9 c , biheteromeric both connexons heteromeric, Figure 9 d , etc. In view of this complexity, we have recently begun addressing questions on CO 2 gating in heteromeric connexons and heterotypic channels.

We think that heteromeric connexons are an excellent tool for learning whether CO 2 gating requires cooperativity among the connexins of a connexon.

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Similarly, heterotypic channels can help determining whether the two connexons of a cell-cell channel influence each other's gating behavior. Our preliminary data indicate that connexin cooperativity within a connexon hemichannel may be necessary If this were true, one would expect physiologically occurring heteromeric hemichannels to gate poorly, resulting in important functional consequences for tissue behavior. Whereas connexin cooperativity within a connexon may be needed for efficient gating, cooperativity between two connexons forming a cell-cell channel may not be necessary.

The chemical gating of gap junction channels appears to be a complex phenomenon that involves more than one connexin domain. Both an increase in cytosolic calcium concentration and a decrease in pH i appear to initiate the cell-cell uncoupling process, but based on our data the effect of low pH i on gap junction channels appears to be primarily mediated by an increase in cytosolic free calcium concentration.

Gap Junction Channels and Hemichannels

At the molecular level, two connexin domains have been considered important: the inner cytoplasmic loop and the carboxy-terminus chain. However, different functions have been attributed to the latter in Cx32 and in Cx The absence of high resolution structural information is the major handicap for understanding channel gating mechanisms at the molecular level. Nonetheless, important information on the gating process will continue to accumulate through connexin chimeras and mutants. A thorough study of relevant connexin domains based on molecular genetics and biophysics, coupled to careful comparisons of connexin sequences and gating behaviors, should provide a good understanding of the molecular mechanism of channel gating even in the absence of a detailed portrait of the three-dimensional architecture of connexin.

Connections with connexins: The molecular basis of direct intercellular signaling. Gap junctions are required for the propagation of spreading depression. Gap junction distribution is altered between cardiac myocytes infected with Trypanosoma cruzi. Peracchia C Structural correlates of gap junction permeation. Molecular models of channel interaction and gating in gap junctions. Molecular and Cellular Physiology.

An electrostatic mechanism for Ca2+-mediated regulation of gap junction channels

Topology of the Mr 27, liver gap junction protein. Topological distribution of two connexin32 antigenic sites in intact and split rodent hepatocyte gap junctions. Biochemical and immunochemical analysis of the arrangement of connexin43 in rat heart gap junction membranes. Membrane topology and quaternary structure of cardiac gap junction ion channels. The topological structure of connexin 26 and its distribution compared to connexin 32 in hepatic gap junctions.

Leube RE Increase in gap junction resistance with acidification in crayfish septate axons is closely related to changes in intracellular calcium but not hydrogen ion concentration. Gap junction gating sensitivity to physiological internal calcium regardless of pH in Novikoff hepatoma cells. Micromolar levels of intracellular calcium reduce gap junctional permeability in lens cultures. Loewenstein WR Permeability of membrane junctions.

Permeability of a cell junction during intracellular injection of divalent cations.

Permeability of a cell junction and the local cytoplasmic free ionized calcium concentration: a study with aequorin. De Mello WC The main types of modulation are:. Connexons play an imperative role in behavior and neurophysiology. Many of the details surrounding their pathological functions remain unknown as research has only begun recently. In the central nervous system CNS , connexons play a major role in conditions such as epilepsy , ischemia , inflammation , and neurodegeneration.

Gap Junction Channels and Hemichannels | Taylor & Francis Group

Along with their key role in the CNS, connexons are crucial in the functioning of cardiac tissues. The direct connection allows for quick and synchronized firing of neurons in the heart which explains the ability for the heart to beat quickly and change its rate in response to certain stimuli.

The mechanism by which connexons aid in these processes is still being researched however, it is currently understood that this mechanism involves purinergic signaling form of extracellular signaling mediated by purine nucleotides and nucleosides such as adenosine and ATP and permeability to ATP. Some of the diseases associated with connexons are cardiovascular disease and diabetes , which is the inability of the body to produce insulin for glucose uptake by cells and degradation in the smaller units of connexons, called connexins, possibly leading to the onset of heart disease.

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Cardiovascular disease and diabetes, type I and II, affects similar locations within cells of the heart and pancreas. This location is the gap junction, where connexons facilitate rapid cell-to-cell interactions via electrical transmissions. Gap junctions are often present at nerve endings such as in cardiac muscle and are important in maintaining homeostasis in the liver and proper function of the kidneys. The gap junction itself is a structure that is a specialized transmembrane protein formed by a connexon hemichannel. In cardiovascular disease, Cx43 connexin 43 , a subunit of a connexon, is a general protein of the gap junction stimulating cardio myocyte muscle cells of intercalated discs facilitating synchronized beating of the heart.

In the occurrence of cardiovascular disease the Cx43 subunit begins to show signs of oxidative stress, the ability of the heart to counteract the buildup of harmful toxins due to age or diet leading to reduced vascular functions. Cx36 connexin 36 subunit mediates insulin excretion and glucose-induced insulin release from gap junctions of the liver and pancreas. The secretion of hormones into the blood stream to target distant organs. However, endocrine signaling in the pancreas and liver operates along short distances in the cellular membrane by way of signaling pathways, ion channels, G-protein coupled receptors , tyrosine-kinase receptors , and cell-to-cell contact.

The Tight fit of the gap junction is such that cells in the tissue can communicate more efficiently and maintain homeostasis. Thus the purpose of the gap junction is to regulate the passage of ions, nutrients, metabolites, second messengers, and small biological molecules. A deficiency of Cx36 adversely affects the ability of the gap junction to operate within these tissues leading a reduction in function and possible disease. Similar symptoms associated with the loss or degradation of the gap junction have been observed in type II diabetes, however, the function of Cx36 in Type 1 and type II diabetes in humans is still unknown.