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Channel blocker

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Tetrodotoxin, an example of a channel block molecule.

Achannel blockeris the biological mechanism in which a particular molecule is used to prevent the opening of ion channels in order to produce aphysiologicalresponse in a cell. Channel blocking is conducted by different types of molecules, such as cations, anions, amino acids, and other chemicals. These blockers act as ion channelantagonists,preventing the response that is normally provided by the opening of the channel.

Ion channelspermit the selective passage of ions through cell membranes by utilizing proteins that function as pores, which allow for the passage of electrical charge in and out of the cell.[1]These ion channels are most often gated, meaning they require a specific stimulus to cause the channel to open and close. These ion channel types regulate the flow of charged ions across the membrane and therefore mediate membrane potential of the cell.

Molecules that act as channel blockers are important in the field of pharmacology, as a large portion of drug design is the use of ion channel antagonists in regulating physiological response. The specificity of channel block molecules on certain channels makes it a valuable tool in the treatment of numerous disorders.[2][3]

Background[edit]

Ion channels[edit]

Main article:Ion channel
Example of voltage-dependent potassium ion channel in relation to changing ion concentrations

To comprehend the mechanism of channel blockers, it is critical to understand the composition of ion channels. Their main function is to contribute to theresting membrane potentialof a cell via the flow ofionsthrough a cell membrane. To accomplish this task, ions must be able to cross the hydrophobic region of alipid bilayermembrane, an unfavorable process. To assist in ion transport, ion channels form a hydrophilic pore through the membrane which allows for the usually unfavorable transfer of hydrophilic molecules.[4]Various ion channels have varying mechanisms of function. They include:

Molecules that act as ion channel blockers can be used in relation to any of these various channels. For example, sodium channels, which are essential to the production ofaction potentials,are affected by many different toxins.Tetrodotoxin(TTX), a toxin found in pufferfish, completely blocks sodium ion transportation by blocking the selectivity filter region of the channel.[5]Much of the structure of the pores of ion channels has been elucidated from studies that used toxins to inhibit channel function.[6][7][8]

Identity[edit]

Tools such asX-ray crystallographyandelectrophysiologyhave been essential in locating the binding sites of open channel block molecules. By studying the biological and chemical makeup of ion channels, researchers can determine the makeup of the molecules that bind to certain regions. X-ray crystallography provides a structural image of the channel and molecule in question.[9]Determining the hydrophobicity of channel domains throughhydrophobicity plotsalso provides clues to the chemical makeup of the molecule and why it binds to a certain region. For example, if a protein binds to a hydrophobic region of the channel (and therefore, has a transmembrane region), the molecule in question might be composed of the amino acidsalanine,leucine,orphenylalanine,as they are all hydrophobic themselves.[10]Electrophysiology is also an important tool in identifying channel structure, as analyzing the ionic factors that lead to channel activation can be critical to understanding the inhibiting actions of open channel block molecules.[3][9]

Physiology[edit]

This diagram of a NMDA receptor shows the binding points for a diverse array of molecules which can affect the receptor function. Legend: 1. Cell membrane 2. Channel blocked by Mg2+at the block site (3) 3. Block site by Mg2+4. Hallucinogen compounds binding site 5. Binding site for Zn2+6. Binding site for agonists(glutamate) and/or antagonist ligands(APV) 7. Glycosylation sites 8. Proton binding sites 9. Glycine binding sites 10. Polyamines binding site 11. Extracellular space 12. Intracellular space

Receptor antagonist[edit]

Channel blockers are antagonists for the respective ion channels. Many channels have binding spots for regulatory elements which can promote or repress normal function depending on the requirements within the cell and organism. The normal function of agonist binding is the generation of cellular changes leading to various downstream effects; these effects range from altering membrane potential to initiation ofsignaling cascades.[11]Conversely, when open channel blockers bind to the cell they prevent the normal function of agonist binding. For example,voltage-gated channelsopen and close based on membrane potential and are critical in the generation of action potentials by their allowance of ions to flow down established gradients. However, open channels blockers can bind to these channels to prevent ions from flowing, thus inhibiting the initiation of an action potential.[12]

Specificity of molecules[edit]

Many differentorganic compoundscan act as channel blockers despite channel specificity. Channels have evolved structures that, due to their membrane spanning regions, can discriminate between various ions or compounds. For example, some objects are too large for to fit into channels that are structurally specified to transport smaller objects, such as a potassium ion attempting to fit into a sodium channel. Conversely, some objects are too small to be properly stabilized by certain channel pores, such as a sodium ion attempting to pass through a potassium channel.[11][13]In both cases, channel flux is not permitted. However, as long as a particular compound possesses adequate chemical affinity to a channel, that compound may be able to bind and block the channel pore. For example, TTX can bind and inactivate voltage-gated sodium channels, despite the fact that TTX is much larger and chemically different than sodium ions. Given the disparities in size and chemical properties between TTX and a sodium ion, this is an example of structure being used to block usually specific channels.[14]

Kinetics[edit]

A channel block can be induced by many different types of organic compounds as long as they can bind to some portion of the target channel's pore. The kinetics of channel blockers are primarily understood though their use asanesthetics.Local anesthetics work by inducing a phasic block state in the targeted neurons.[13]Initially, open channel blockers do not effectively prevent action potentials, as few channels are blocked and the blocker itself can be released from the channel either quickly or slowly depending on its characteristics. However, phasic blocks occur as repeated depolarization increases blockers’ affinity for channels in the neuron. The combination of an increase in available channels and the change in channel conformation to increase blocker binding affinity are responsible for this action.[13][15][16]

Clinical significance[edit]

Therapeutic uses[edit]

Variousneurodegenerative diseaseshave been associated with excessiveNMDA receptoractivation meant to mediate calcium dependentneurotoxicity.Researchers have examined many different NMDA antagonists and their therapeutic efficacy, none of which have concluded to be both safe and effective.[17]For years, researchers have been investigating the effects of an open channel block,memantine,as a treatment option for neurotoxicity. They have hypothesized that the faster blocking and unblocking rates, and overall kinetics, of memantine could be the underlying reason for the clinical tolerance.[17][3]As an uncompetitive antagonist, memantine should bring NMDA levels close to normal despite highglutamateconcentration. Based on this information, researchers have speculated that someday memantine could be used as an open channel block to prevent increasing glutamate levels associated with neurotoxicity with few to no side effects compared to other treatment options.[17]

Alzheimer's disease[edit]

Alzheimer's disease,a specific neurodegenerative disorder, is linked toglutaminergicneurotransmissioninterruptions that are believed to result in the staple cognitive symptoms of Alzheimer's.[18][2][3]Researchers suggest that noncompetitive NMDA receptor agonists can be used to aid in the management of these symptoms without producing severe side effects.[18]As one of the only drugs approved for Alzheimer's treatment, memantine has been shown to allow excitatory post-synaptic currents to remain unaffected while decreasing the incidence and amplitude of inhibitory post-synaptic currents.[19]Evidence supports the hypothesis that both the strong voltage dependency and fast kinetics of memantine may be responsible for the decreased side effects and cognitive progress.[20]

Cystic fibrosis[edit]

Cystic fibrosisis a progressive, genetic disease that is linked to CF transmembrane regulator (CFTR) dysfunction.[21]Blockage of this channel by certain cytoplasmic, negatively-charged substances results in reduced chloride ion and bicarbonate anion transport, as well as reduced fluid and salt secretion. This results in a buildup of thick mucus, which is characteristic of cystic fibrosis.[21]

Pharmacology[edit]

Anesthetics[edit]

Channel blockers are essential in the field of anesthetics. Sodium channel inhibitors are used as bothantiepilepticsandantiarrhythmics,as they can inhibit the hyper-excitable tissues in a patient.[22]Introducing specific sodium channel blockers into a tissue allows for the preferential binding of the blocker to sodium channels, which results in an ultimate inhibition of the flow of sodium into the tissue. Over time, this mechanism leads to an overall decrease in tissue excitation. Prolonged hyperpolarization interrupts normal channel recovery and allows for constant inhibition, providing dynamic control of the anesthetics in a given setting.[22]

Alzheimer's disease[edit]

Excessive exposure to glutamate leads to neurotoxicity in patients with Alzheimer's disease. Specifically, over-activation of NMDA-type glutamate receptors have been linked to neural cell excitotoxicity and cell death.[18][2]A potential solution to this is a decrease in NMDA receptor activity, without interfering so drastically as to cause clinical side effects.[23]

In an attempt to prevent further neurodegeneration, researchers have used memantine, an open channel block, as a form of treatment. Thus far, the use of memantine in patients with Alzheimer's disease quickly results in clinical progress across many different symptoms. Memantine is thought to work effectively due to its ability to quickly modify its kinetics, which prevents buildup in the channel and allows normal synaptic transmission. Other channel blockers have been found to block all NMDA receptor activity, leading to adverse clinical side effects.[3]

CFTR channel dysfunction[edit]

Cystic Fibrosis transmembrane regulators (CFTRs) function in chloride ion, bicarbonate anion, and fluid transport.[24]They are expressed primarily in apical membranes ofepithelialcells in respiratory, pancreatic, gastrointestinal, and reproductive tissues.[21][24]Abnormally-elevated CFTR function results in excessive fluid secretion. High-affinity CFTR inhibitors, such as CFTRinh-172 and GlyH-101, have been shown to be efficient in treatment of secretory diarrheas.[25][26]Theoretically, CFTR channel blockers may also be useful as male contraceptives. CFTR channels mediate bicarbonate anion entry which is essential for spermcapacitation.[27]

Various types of substances have been known to block CFTR chloride ion channels. Some of the best-known and studied substances include sulfonylureas, arylaminobenzenoates, and disulfonic stilbenes.[28][29][30]These blockers are side-dependent as they enter the pore exclusively from the cytoplasmic side, voltage-dependent as hyperpolarized membrane potentials favor negatively-charged substance entry into the pore from the cytoplasmic side, and chloride ion concentration-dependent as high extracellular chloride ions electrostatically repel negatively-charged blockers back into the cytoplasm.[31]

Types[edit]

There are several different major classes of channel blockers, including:

The following types which act onligand-gated ion channels(LGICs) via binding to their pore also exist:

Channel blockers are also known to act atAMPA receptors,Glycine receptors,Kainate receptors,P2X receptorsandZinc (Zn2+)-activated channels.The type of inhibition mediated by channel blockers may be referred to asnoncompetitiveoruncompetitive.

See also[edit]

References[edit]

  1. ^"Medical Definition of Ion channel".MedicineNet.Retrieved2017-03-20.
  2. ^abcKocahan S, Doğan Z (February 2017)."Mechanisms of Alzheimer's Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors".Clinical Psychopharmacology and Neuroscience.15(1): 1–8.doi:10.9758/cpn.2017.15.1.1.PMC5290713.PMID28138104.
  3. ^abcdeLipton SA (January 2004)."Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults".NeuroRx.Neuroprotection.1(1): 101–10.doi:10.1602/neurorx.1.1.101.PMC534915.PMID15717010.
  4. ^Ahern CA, Payandeh J, Bosmans F, Chanda B (January 2016)."The hitchhiker's guide to the voltage-gated sodium channel galaxy".The Journal of General Physiology.147(1): 1–24.doi:10.1085/jgp.201511492.PMC4692491.PMID26712848.
  5. ^Moore JW, Blaustein MP, Anderson NC, Narahashi T (May 1967)."Basis of tetrodotoxin's selectivity in blockage of squid axons".The Journal of General Physiology.50(5): 1401–11.doi:10.1085/jgp.50.5.1401.PMC2225715.PMID6033592.
  6. ^Stevens M, Peigneur S, Tytgat J (2011-11-09)."Neurotoxins and their binding areas on voltage-gated sodium channels".Frontiers in Pharmacology.2:71.doi:10.3389/fphar.2011.00071.PMC3210964.PMID22084632.
  7. ^Miller C (December 1988). "Competition for block of a Ca2(+)-activated K+ channel by charybdotoxin and tetraethylammonium".Neuron.1(10): 1003–6.doi:10.1016/0896-6273(88)90157-2.PMID2483092.S2CID32262373.
  8. ^Aiyar J, Withka JM, Rizzi JP, Singleton DH, Andrews GC, Lin W, Boyd J, Hanson DC, Simon M, Dethlefs B (November 1995)."Topology of the pore-region of a K+ channel revealed by the NMR-derived structures of scorpion toxins".Neuron.15(5): 1169–81.doi:10.1016/0896-6273(95)90104-3.PMID7576659.
  9. ^abFindeisen F, Campiglio M, Jo H, Abderemane-Ali F, Rumpf CH, Pope L, Rossen ND, Flucher BE, DeGrado WF, Minor DL (March 2017)."Stapled Voltage-Gated Calcium Channel (CaV) α-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function".ACS Chemical Neuroscience.8(6): 1313–1326.doi:10.1021/acschemneuro.6b00454.PMC5481814.PMID28278376.
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  11. ^abJackson MB (February 2010)."Open channel block and beyond".The Journal of Physiology.588(Pt 4): 553–4.doi:10.1113/jphysiol.2009.183210.PMC2828128.PMID20173077.
  12. ^Ahern CA, Payandeh J, Bosmans F, Chanda B (January 2016)."The hitchhiker's guide to the voltage-gated sodium channel galaxy".The Journal of General Physiology.147(1): 1–24.doi:10.1085/jgp.201511492.PMC4692491.PMID26712848.
  13. ^abcButterworth JF, Strichartz GR (April 1990)."Molecular mechanisms of local anesthesia: a review".Anesthesiology.72(4): 711–34.doi:10.1097/00000542-199004000-00022.PMID2157353.S2CID8277924.
  14. ^Evans MH (September 1969). "Mechanism of saxitoxin and tetrodotoxin poisoning".British Medical Bulletin.25(3): 263–7.doi:10.1093/oxfordjournals.bmb.a070715.PMID5812102.
  15. ^Mert T, Gunes Y, Guven M, Gunay I, Ozcengiz D (March 2002). "Comparison of nerve conduction blocks by an opioid and a local anesthetic".European Journal of Pharmacology.439(1–3): 77–81.doi:10.1016/S0014-2999(02)01368-7.PMID11937095.
  16. ^Mitolo-Chieppa D, Carratu MR (May 1983). "Anaesthetic drugs: electrophysiological bases of their conduction blocking effect".Pharmacological Research Communications.15(5): 439–50.doi:10.1016/s0031-6989(83)80064-2.PMID6351107.
  17. ^abcChen HS, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE, Lipton SA (November 1992)."Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity".The Journal of Neuroscience.12(11): 4427–36.doi:10.1523/JNEUROSCI.12-11-04427.1992.PMC6576016.PMID1432103.
  18. ^abcMüller WE, Mutschler E, Riederer P (July 1995). "Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer's dementia".Pharmacopsychiatry.28(4): 113–24.doi:10.1055/s-2007-979603.PMID7491365.S2CID260240191.
  19. ^Povysheva NV, Johnson JW (December 2016)."Effects of memantine on the excitation-inhibition balance in prefrontal cortex".Neurobiology of Disease.96:75–83.doi:10.1016/j.nbd.2016.08.006.PMC5102806.PMID27546057.
  20. ^Dominguez, Evangelyn; Chin, Ting-Yu; Chen, Chih-Ping; Wu, Tzong-Yuan (2011-12-01)."Management of moderate to severe Alzheimer's disease: Focus on memantine".Taiwanese Journal of Obstetrics and Gynecology.50(4): 415–423.doi:10.1016/j.tjog.2011.10.004.ISSN1028-4559.PMID22212311.
  21. ^abcLubamba B, Dhooghe B, Noel S, Leal T (October 2012). "Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy".Clinical Biochemistry.45(15): 1132–44.doi:10.1016/j.clinbiochem.2012.05.034.PMID22698459.
  22. ^abRamos E, O'leary ME (October 2004)."State-dependent trapping of flecainide in the cardiac sodium channel".The Journal of Physiology.560(Pt 1): 37–49.doi:10.1113/jphysiol.2004.065003.PMC1665201.PMID15272045.
  23. ^Lipton SA (May 2007). "Pathologically-activated therapeutics for neuroprotection: mechanism of NMDA receptor block by memantine and S-nitrosylation".Current Drug Targets.8(5): 621–32.doi:10.2174/138945007780618472.PMID17504105.
  24. ^abFrizzell RA, Hanrahan JW (June 2012)."Physiology of epithelial chloride and fluid secretion".Cold Spring Harbor Perspectives in Medicine.2(6): a009563.doi:10.1101/cshperspect.a009563.PMC3367533.PMID22675668.
  25. ^Muanprasat C, Sonawane ND, Salinas D, Taddei A, Galietta LJ, Verkman AS (August 2004)."Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure-activity analysis, and in vivo efficacy".The Journal of General Physiology.124(2): 125–37.doi:10.1085/jgp.200409059.PMC2229623.PMID15277574.
  26. ^Ma T, Thiagarajah JR, Yang H, Sonawane ND, Folli C, Galietta LJ, Verkman AS (December 2002)."Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion".The Journal of Clinical Investigation.110(11): 1651–8.doi:10.1172/JCI16112.PMC151633.PMID12464670.
  27. ^Chen H, Ruan YC, Xu WM, Chen J, Chan HC (2012-11-01)."Regulation of male fertility by CFTR and implications in male infertility".Human Reproduction Update.18(6): 703–13.doi:10.1093/humupd/dms027.PMID22709980.
  28. ^Schultz BD, DeRoos AD, Venglarik CJ, Singh AK, Frizzell RA, Bridges RJ (August 1996). "Glibenclamide blockade of CFTR chloride channels".The American Journal of Physiology.271(2 Pt 1): L192-200.doi:10.1152/ajplung.1996.271.2.L192.PMID8770056.
  29. ^Zhang ZR, Zeltwanger S, McCarty NA (May 2000). "Direct comparison of NPPB and DPC as probes of CFTR expressed in Xenopus oocytes".The Journal of Membrane Biology.175(1): 35–52.doi:10.1007/s002320001053.PMID10811966.S2CID19341540.
  30. ^Linsdell P, Hanrahan JW (November 1996)."Disulphonic stilbene block of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in a mammalian cell line and its regulation by a critical pore residue".The Journal of Physiology.496(Pt 3): 687–93.doi:10.1113/jphysiol.1996.sp021719.PMC1160856.PMID8930836.
  31. ^Linsdell P (February 2014)."Cystic fibrosis transmembrane conductance regulator chloride channel blockers: Pharmacological, biophysical and physiological relevance".World Journal of Biological Chemistry.5(1): 26–39.doi:10.4331/wjbc.v5.i1.26.PMC3942540.PMID24600512.
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