Gap junction modulation
Gap junction modulation describes the functional manipulation of gap junctions, specialized channels that allow direct electrical and chemical communication between cells without exporting material from the cytoplasm.[1] Gap junctions play an important regulatory role in various physiological processes including signal propagation in cardiac muscles and tissue homeostasis of the liver. Modulation is required, since gap junctions must respond to their environment, whether through an increased expression or permeability. Impaired or altered modulation can have significant health implications and are associated with the pathogenesis of the liver, heart and intestines.[2][3][4]
Modulation is achieved by endogenous chemicals, growth factors, hormones and proteins that affect gap junction expression, structure, degradation and permeability. Natural forms of modulation include voltage gating and chemical modulation. Voltage-gating is a relatively fast modulation categorized into Vj gating and slow voltage gating, which are further influenced by calcium ions (Ca2+), pH and calmodulin (CaM).[1][5] Chemical modulation entails the addition or removal of a functional group or protein from the connexin subunits of gap junctions; this can alter gap junction expression and structure.[6]
Voltage gating
The molecular structure of gap junctions makes them sensitive and responsive to intercellular currents.[7] This sensitivity allows the channel to alter its size and structure according to electrical signals. The two types of voltage gating, Vj gating and slow voltage gating, are similar in their mechanisms, but react to different electrical magnitudes.[7] The electrical signals that modulate gap junctions release calcium ions that has a positive feedback on voltage gating.[8] This calcium modulation is also influenced by pH and Calmodulin(CaM).[8]
Mechanism
Vj gating
Vj gating governs the size of the gap junction, being able to reduce the channel size by up to 40% from its fully open state.[1][7] The sensitivity towards voltage is largely attributed to the gap junction’s cytoplasmic NH2-terminal which is responsive to small voltages (2-3mV).[7][9] Voltage gating modulation is associated with the charge of connexin; positively charged connexin close with hyperpolarization and negatively charged connexins close with depolarization.[7] Other than connexin charge, Vj gating is also regulated by different concentrations of Ca2+, H+ and Calmodulin (CaM).[8]
Slow voltage gating
Slow voltage gating is hypothesized to be similar to Vj gating in terms of mechanism, but unlike Vj gating, fully closes the channel to a non-conducting state.[7] This modulation is slower than the prior gating method, as it occurs in response to Vj gating.[7] The temporal voltage regulation is also subject to higher voltage (10-30mV),[7] various natural factors–such as lipophiles and low pH–and the docking of two hemichannels.[7] The exact mechanisms of both Vj gating and slow voltage gating remain unknown, but it is predicted that change in charge causes the cytoplasmic NH2-terminal domain to move toward the cytoplasm to decrease the pore size.[7]
Factors
Calcium
Calcium exists in organisms in the form of the ion, Ca2+, and is an effective modulator of gap junctions. An increase in calcium ion concentration of above 500nM, the permeability of plasma membrane decreases rapidly.[5] This modulation via calcium is known to be protective, as it prevents dead cells from affecting neighboring cells.[10] Yet, high Ca2+ concentration is rarely seen, as this gating method is self-inhibiting.[8] It has been found that calcium modulation and voltage gating are closely related, as the entry of Ca2+ into cells is more effective in modulating gap junction than the release of Ca2+ from internal store, and the increase in Ca2+ concentration via Ca2+ entry results in depolarization.[8]
pH
Gap junction permeability is further influenced by their environment’s pH. The pH sensitivity depends on the type of connexin composing the gap junction, but the channels generally close at a pH of 6.4-6.2.[8][10] Under weak acidic conditions, the gap junction’s channels are observed to remain closed despite voltage changes, while under strong acidic conditions, the channels do open with voltage, but close immediately.
Reports further indicate a synergistic relationship between hydrogen ions and the intracellular concentration of calcium in reducing gap junction permeability.[8][10] Studies on cardiac cells noted that acidosis, decreased pH, by itself had a limited effect in reducing dye diffusion between cells; the reduction was elevated significantly with an increase in intracellular calcium concentration.[8]
Calmodulin
Calmodulin (CaM) is a protein present in connexin that possesses two Ca2+ binding sites and is composed of 148 amino acids.[8][10] With the binding of Ca2+, calmodulin goes through a conformational change that eventually blocks the gap junction’s channel, preventing the passage of cytoplasmic material. Likewise, while the inhibition of calmodulin expression increases the probability of gap junction closure, CaM-antagonist and CaM-blockers promote the opening of gap junctions.[5][8]
Chemical modification
See also
References
- ^ a b c "Cell - Gap junctions". Encyclopedia Britannica. Retrieved 2020-04-27.
- ^ Noorman, Maartje; van der Heyden, Marcel A.G.; van Veen, Toon A.B.; Cox, Moniek G.P.J.; Hauer, Richard N.W.; de Bakker, Jacques M.T.; van Rijen, Harold V.M. (2009-04-01). "Cardiac cell–cell junctions in health and disease: Electrical versus mechanical coupling". Journal of Molecular and Cellular Cardiology. 47 (1): 23–31. doi:10.1016/j.yjmcc.2009.03.016. ISSN 0022-2828.
- ^ Hoagland, Daniel T.; Santos, Webster; Poelzing, Steven; Gourdie, Robert G. (2019-07-01). "The role of the gap junction perinexus in cardiac conduction: Potential as a novel anti-arrhythmic drug target". Progress in Biophysics and Molecular Biology. Physics meets medicine - at the heart of active matter. 144: 41–50. doi:10.1016/j.pbiomolbio.2018.08.003. ISSN 0079-6107. PMC 6422736. PMID 30241906.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Hernández-Guerra, Manuel; Hadjihambi, Anna; Jalan, Rajiv (2018-12-29). "Gap junctions in liver disease: Implications for pathogenesis and therapy". Journal of Hepatology. 70 (4): 759–772. doi:10.1016/j.jhep.2018.12.023. ISSN 0168-8278.
- ^ a b c Peracchia, Camillo,. Gap junction structure and chemical regulation : direct calmodulin role in cell-to-cell channel gating. London, United Kingdom. ISBN 978-0-12-816380-1. OCLC 1086610350.
{{cite book}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link) - ^ Segretain, Dominique; Falk, Matthias M. (2004-03-23). "Regulation of connexin biosynthesis, assembly, gap junction formation, and removal". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1662 (1–2): 3–21. doi:10.1016/j.bbamem.2004.01.007.
- ^ a b c d e f g h i j Harris, Andrew L. (2002-02-01). "Voltage-sensing and Substate Rectification". Journal of General Physiology. 119 (2): 165–170. doi:10.1085/jgp.119.2.165. ISSN 1540-7748. PMC 2233797. PMID 11815666.
{{cite journal}}: CS1 maint: PMC format (link) - ^ a b c d e f g h i j Peracchia, Camillo (2004-03-23). "Chemical gating of gap junction channels". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1662 (1–2): 61–80. doi:10.1016/j.bbamem.2003.10.020.
- ^ Brink, Peter (2000-07-01). "Gap Junction Voltage Dependence". Journal of General Physiology. 116 (1): 11–12. doi:10.1085/jgp.116.1.11. ISSN 0022-1295. PMC 2229614. PMID 10871636.
{{cite journal}}: CS1 maint: PMC format (link) - ^ a b c d Nielsen, Morten Schak; Nygaard Axelsen, Lene; Sorgen, Paul L.; Verma, Vandana; Delmar, Mario; Holstein-Rathlou, Niels-Henrik (2012-07-01), Terjung, Ronald (ed.), "Gap Junctions", Comprehensive Physiology, John Wiley & Sons, Inc., pp. c110051, doi:10.1002/cphy.c110051, ISBN 978-0-470-65071-4, PMC 3821273, PMID 23723031, retrieved 2020-04-27
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