Gap junction modulator
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Gap Junction Modulators
Gap junction modulators are compounds or agents that either facilitate or inhibit the transfer of small molecules between biological cells by regulating gap junctions. Many different molecules act as modulators in gap junctions, from simple ions to complex proteins. endogenous chemicals, growth factors, hormones and proteins that affect gap junction expression, structure, degradation and permeability[1][2]. Both excitable and non-excitable cells in bodily tissues include gap junctions, which are widely distributed and crucial to embryonic development[3].
Various physiological processes including cardiac, neural or auditory, depend on gap junctions to perform crucial regulatory roles, and the modulators themselves are the key players in this procedure[2][4][5][6]. Gap junctions are necessary for diffusion of small molecules from cell to cell, keeping the cells interlinked and connecting the cytoplasm, allowing transfer of signals or resources between the body[1][2]. These modulators can be potential therapeutic targets for a number of disorders and are essential in the regulation of several physiological processes[2][7].
Categories
Protein kinases
Protein kinases moderate phosphorylation, the addition of phosphate groups, to the junction proteins play important roles in controlling the junction protein and their possible subunits[8][9][10].
These kinases, such as PKA and PKC, phosphorylate the connexin gap junctions in the heart[8][10][11]. Phosphate group addition changes the charge and configuration of the connexin protein, opening (for PKA) and closing (for PKC) the transmembrane channel pores[8][11]. Dephosphorylation of these same proteins by phosphatase enzymes reverses these processes, reopening or reclosing the connexin pores[8][9].
Chemical gating
Calmodulin
Calmodulin is a model Ca2+ sensor that is very adaptable, and its high-affinity Ca2+ binding domains are EF-hands[13][14]. All eukaryotic cells contain calmodulin, which mediates Ca2+-dependent signaling[13][14][15]. Calmodulin conformationally varies upon binding Ca2+ to form complexes with a wide range of target proteins[13][15].
Gap junction channels are inhibited by intracellular Ca2+-activated calmodulin (CaM) in the low nM to high μM range of [Ca2+]i[13][15]. This control is critical for several cellular functions, such as lens transparency, heart contraction synchronization, and hearing[3][4][15][16].
Calmodulin protein, modelled using pyMOL. pyMOL protein code taken from Protein Data Bank[17]
Calcium
Calcium ions are a major modulator that can completely close the gap junction proteins[13][18]. Ca2+ ions binding to the amino acid side chains changes the structure of the protein, decreasing connectivity of other molecules[14]. Calcium affects not only connexin, but also Calmodulin, a transmembrane protein present in all eukaryotic cells[14][18]. Calcium ions are fairly abundant in cells, as they are the main signal ion of the nervous system, where the calcium released by the nervous signals can inform the junction of proteins of changes needed to adapt to their surroundings[5][[13]. Ca2+ itself is associated with cell-to-cell uncoupling, which breaks apart the pathway between cells when the pathway itself becomes harmful, such as pathways to injured cells, as the abnormal pathways and communication between injured cells can cause various disorders[14][16][[18].
pH changes
Changes in the pH of the environment to a more acidic or alkaline one can also affect the gap junction protein structure, changing their shape which closes the diffusion pathways[12][19]. These pH changes are caused by chemical reactions from other metabolic processes or even inflammation signals from disease or the body’s immune system[12][18][19[. Significant pH changes are acidification, the addition of hydrogen ions, and alkalinization, the removal of hydrogen ions[20]. Higher pH is associated with the closing of the gap junction channels, either by protonation of amino acids which can change the entire protein structure, or in some cases even denaturing the whole protein if pH is too low, completely preventing passage of molecules through the gap junctions[18][19].
Functionality
Gap junction enhancers (GJEs)
By increasing gap junction coupling, these modulators facilitate cell-to-cell communication[2][7]. Examples include growth factors like TGF-beta and EGF, which are important in wound healing and tissue repair, and retinoic acid, which plays a part in cellular differentiation[2][21][22].
Gap junction inhibitors (GJIs)
By lowering gap junction coupling, these modulators lessen communication between cells[2][7]. Among them are the anti-inflammatory and anti-tumor effects of 18-alpha-glycyrrhetinic acid (18-AGA) and carbenoxolone, which are used to treat inflammatory diseases[23][24].
Connexin (Cx) specific modulators
The building blocks of gap junction channels, known as connexin proteins, are the target of these modulators. Gap26 and Gap27, two Cx43 mimetic peptides that selectively block Cx43-based gap junctions, are two examples[8][10][12].
Voltage-dependent modulators
These modulators modify the cell membrane potential, which has an impact on gap junctions[19]. For instance, substances like heptanol and quinine can interfere with gap junctions' ability to sense voltage, which inhibits the junctions[25][26].
Natural compounds
There have been reports of several natural substances, including flavonoid, modulating gap junction activity[27][28]. For instance, it has been demonstrated that the dietary flavonoid quercetin inhibits gap junction communication in specific cell types[27][28].
Pharmaceutical agents
It has been discovered that a number of pharmacological medications either primarily work by modulating gap junction function or have this effect as an unintended side effect[25][27][29]. Medications that either block gap junction communication include amiodarone, an antiarrhythmic, and cisplatin, an anti-cancer medication; or facilitate gap junction conductance, such as rotigaptide and danegaptide[30][31][32][33].
Rotigaptide and danegaptide
Recently, the modulators were found to be effective as an antidote to toxicity caused by overdose of certain drugs, such as Bupropion[29][32]. Bupropion is an antidepressant, but is also a cardiotoxin if ingested in large doses[29]. Rotigaptide and danegaptide, two small-molecule medications that increase gap junction conductance by facilitating gap junction activity, can prevent the binding or passing of bupropion to the cardiac gap junctions[29][32][33]. Thus the modulators can be essential to preventing overdose of bupropion[29]. Investigating these compounds in overdose scenarios with bupropion may help meet the pressing need for novel strategies to reduce bupropion-induced cardiotoxicity.
Tonabersat
Migraine, a neurovascular disorder causing recurrent headaches, results from abnormal sensory processing due to peripheral and/or central sensitization[34][35]. Cortical Spreading Depression (CSD) underlies migraine aura and may trigger pain, relying on neuronal-glial cell communication through connexin-containing gap junctions and hemichannels[5][10][34]. These processes contribute to sensitization within the trigeminal ganglion. The novel benzopyran compound, tonabersat, selectively binds to a unique brain site, α2δ-1 subunit of voltage-gated calcium channels, reducing calcium intake[35][36]. This binding reduces CSD and inhibits gap-junction communication in preclinical studies, so these findings indicate tonabersat's potential for preventing migraine attacks[35][36].
See also:
References:
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36. Silberstein S. Tonabersat, a novel gap-junction modulator for the prevention of Migraine. Cephalalgia. 2009;29(2_suppl):28–35. doi:10.1111/j.1468-2982.2009.01973.x Click on your username in the top right hand corner of this page. You should see it if you are logged into Wikipedia. This will take you to your User page. Add the purpose statement to that page. This is your sandbox. Not your User page. It's confusing I know.