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Tetrodotoxin, an example of an open channel block molecule.

An open channel block is the biological mechanism of blocking open ion channels in order to produce a physiological response in a cell. Open channel blocks are conducted by open channel blockers, which consist of various classes of molecules such as cations, anions, amino acids, and other chemicals. These blockers act as ion channel antagonists, preventing the response that is normally provided by the opening of the channel.

Ion channels permit 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. Certain channels called ligand-gated ion channels are mediated by the binding of a specific channel protein. Others, known as voltage-gated channels, open and close in response to a change in the membrane potential.[2] Ultimately, both of 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 open 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.

Identity

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Ion channels

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Main article: Ion channel

Example of voltage-dependent potassium ion channel in relation to changing ion concentrations

Understanding the composition of ion channels is critical to comprehend the mechanism of open channel block. Their main function is to contribute to the resting membrane potential of a cell via the flow of ions through a cell membrane. To accomplish this task, ions must be able to cross the hydrophobic region of a lipid bilayer membrane. Ion channels form a hydrophilic pore through the membrane which allows for the usually unfavorable transfer of hydrophilic molecules.[3] Various ion channels have varying mechanism of function. They include:

Molecules that act as open channel blockers can be used in relation to any of these various channels. For example, sodium channels, which are essential to the production of action potentials, are affected by many different toxins. Tetrodotoxin (TTX), a toxin found in pufferfish, completely blocks sodium transportation by blocking the selectivity filter region of the channel.[4] Much of the structure of the pores of ion channels has been elicited from such studies using toxins that inhibit channel function.

Binding of open channel blockers and channel structure

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Tools such as X-ray crystallography and electrophysiology have been essential to 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 an structural image of the channel and molecule in question.[5] Determining the hydrophobicity of channel domains through hydrophobicity plots also provides a clue as 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 acids alanine, leucine, or phenylalanine, as they are hydrophobic themselves.[6] Electrophysiology can also be an important tool, as analyzing the ionic factors that lead to channel activation can be critical to understanding the inhibiting actions of open channel block molecules.

Physiology

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Receptor antagonist

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Open channel blockers are antagonists for the channels required for normal function within many cells. Many channels have binding spots for regulatory elements or normal function depending on their role within the cell. During normal function, these agonists bind to the receptors or channels on the cell membrane, inducing changes and leading to various effects, which range from changing the membrane potential to initiating signal cascades.[7] Conversely, when open channel blockers bind to the cell they prevent normal function. For example, voltage-gated channels open 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.[8] 

Specificity of molecules

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Many different organic compounds can act as open channel blockers despite channel specificity. Channels have evolved structures that, due to their membrane spanning regions, can discriminate between various ions or compounds. Some objects are too large for to fit into channels that are structurally specified to transport smaller objects, whereas some objects are too small to be properly stabilized by certain channel pores.[7][9] 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, tetrodotoxin (TTX) can bind and inactivate voltage-gated sodium channels. This shows that TTX is much larger and chemically different than sodium ions.[10] This is an example of structure being used to block usually specific channels.

Kinetics

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An open channel block can be caused by many different types of organic compounds as long as they can bind to some portion of the target channels pore. The kinetics of open channel blockers are primarily understood though their use as anesthetics. Local anesthetics work by inducing a phasic block state in the targeted neurons.[9] 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. However, phasic blocks occur as repeated depolarization increases blockers’ affinity for channels in the neuron.[9][11][12] The combination of an increase in available channels and the change in channel conformation to increase blocker binding affinity are responsible for this action.

Therapeutic uses

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The specificity of open channel block molecules on certain channels makes it a valuable tool in the treatment of numerous disorders. Various neurodegenerative diseases have been associated with excessive NMDA receptor activation meant to mediate calcium dependent neurotoxicity. Researchers have examined many different NMDA antagonists and their therapeutic efficacy, none of which have concluded to be both safe and effective.[13] For years, researchers have been investigating the effects of an open channel block, memantine, on as a treatment option for neurotoxicity. They hypothesized that the faster blocking and unblocking rates, and overall kinetics, of memantine could be the underlying reason for the clinical tolerance.[13][14] As an uncompetitive antagonist, memantine ought to bring NMDA levels close to normal despite high glutamate concentration. Based on this information, researchers speculated some day memantine could be used as an open channel block to prevent increasing glutamate levels associated with neurotoxicity with little to no side effects compared to other treatment options.[13]

Alzheimer's disease

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Alzheimer's disease, a specific neurodegenerative disorder, is linked to glutaminergic neurotransmission interruptions that are believed to result in the staple cognitive issues of Alzheimer's.[15][16][14] Researchers suggest that noncompetitive NMDA receptor agonists can be used to aid in the management of these symptoms without producing severe side effects.[15] 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.

Cystic fibrosis

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Cystic fibrosis is a progressive, genetic disease that is linked to CF transmembrane regulator (CFTR) disfunction.[17] 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, characteristic of cystic fibrosis.

Many 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.[18][19][20] 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.[21]

Pharmacology

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Anesthetics

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Open channel blockers are essential in the field of anesthetics. Sodium channel inhibitors are used as both anti-epileptics and antiarrhythmics, as they can inhibit the hyper-excitable tissues in a patient.[22] Introducing specific types of open channel blocks allows for preferential binding of the block to the channels which results in an ultimate inhibition of the flow of sodium, leading to an overall decrease in tissue excitation. Prolonged hyperpolarization interrupts normal channel recovery and allows for constant inhibition, providing dynamic control of the anesthetics.

Alzheimer's disease

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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.[15][16] A potential solution to this is a decrease in NMDA receptor activity, without interfering so drastically as to cause clinical side effects.

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 so well due to it's ability to quickly modify its kinetics, which prevents buildup in the channel and allows normal synaptic transmission. Other open channel blockers have been found to block all NMDA receptor activity, leading to adverse clinical side effects.[14]

CFTR channel disfunction

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Cystic Fibrosis transmembrane regulators (CFTRs) function in chloride ion, bicarbonate anion, and fluid transport.[23] They are expressed primarily in apical membranes of epithelial cells in respiratory, pancreatic, gastrointestinal, and reproductive tissues.[17][23] 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.[24][25] Theoretically, CFTR channel blockers may also be useful as male contraceptives. CFTR channels mediate bicarbonate anion entry which is essential for sperm capacitation.[26]

Alzheimer’s Disease (management of moderate to severe Alzheimer’s disease; focus on memantine - Dominguez E.) (Pathologically-activated therapeutics for neuroprotection: mechanism of NMDA receptor block by memantine and S-nitrosylation - Lipton SA)

http://www.sciencedirect.com/science/article/pii/S1545534306700104

See also

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  1. ^ "Medical Definition of Ion channel". MedicineNet. Retrieved 2017-03-20.
  2. ^ "ion channel | biology". Encyclopedia Britannica. Retrieved 2017-03-20.
  3. ^ Ahern, Christopher A.; Payandeh, Jian; Bosmans, Frank; Chanda, Baron (2016-01-01). "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. ISSN 0022-1295. PMC 4692491. PMID 26712848.
  4. ^ Moore, John W.; Blaustein, Mordecai P.; Anderson, Nels C.; Narahashi, Toshio (1967-05-01). "Basis of Tetrodotoxin's Selectivity in Blockage of Squid Axons". The Journal of General Physiology. 50 (5): 1401–1411. doi:10.1085/jgp.50.5.1401. ISSN 0022-1295. PMID 6033592.
  5. ^ Findeisen, Felix; Campiglio, Marta; Jo, Hyunil; Abderemane-Ali, Fayal; Rumpf, Christine H.; Pope, Lianne; Rossen, Nathan D.; Flucher, Bernhard E.; DeGrado, William F. (2017-03-09). "Stapled Voltage-Gated Calcium Channel (CaV) α-Interaction Domain (AID) Peptides Act As Selective Protein–Protein Interaction Inhibitors of CaV Function". ACS Chemical Neuroscience. doi:10.1021/acschemneuro.6b00454.
  6. ^ Phoenix, David A.; Harris, Frederick (2002-01-01). "The hydrophobic moment and its use in the classification of amphiphilic structures (review)". Molecular Membrane Biology. 19 (1): 1–10. ISSN 0968-7688. PMID 11989818.
  7. ^ a b Jackson, Meyer B (2010-02-15). "Open channel block and beyond". The Journal of Physiology. 588 (Pt 4): 553–554. doi:10.1113/jphysiol.2009.183210. ISSN 0022-3751. PMC 2828128. PMID 20173077.
  8. ^ Ahern, Christopher A.; Payandeh, Jian; Bosmans, Frank; Chanda, Baron (2016-01-01). "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. ISSN 1540-7748. PMC 4692491. PMID 26712848.
  9. ^ a b c Butterworth, J. F.; Strichartz, G. R. (1990-04-01). "Molecular mechanisms of local anesthesia: a review". Anesthesiology. 72 (4): 711–734. ISSN 0003-3022. PMID 2157353.
  10. ^ EVANS, M. H. (1969-09-01). "MECHANISM OF SAXITOXIN AND TETRODOTOXIN POISONING". British Medical Bulletin. 25 (3): 263–267. doi:10.1093/oxfordjournals.bmb.a070715. ISSN 0007-1420.
  11. ^ Mert, Tufan; Gunes, Yasemin; Guven, Mustafa; Gunay, Ismail; Ozcengiz, Dilek (2002-03-29). "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.
  12. ^ Mitolo-Chieppa, D.; Carratu, M. R. (1983-05-01). "Anaesthetic drugs: electrophysiological bases of their conduction blocking effect". Pharmacological Research Communications. 15 (5): 439–450. ISSN 0031-6989. PMID 6351107.
  13. ^ a b c Chen, H. S.; Pellegrini, J. W.; Aggarwal, S. K.; Lei, S. Z.; Warach, S.; Jensen, F. E.; Lipton, S. A. (1992-11-01). "Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity". Journal of Neuroscience. 12 (11): 4427–4436. ISSN 0270-6474. PMID 1432103.
  14. ^ a b c Lipton, Stuart A. (2004-01-01). "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): 101–110. doi:10.1602/neurorx.1.1.101. PMC 534915. PMID 15717010.
  15. ^ a b c Müller, W.; Mutschler, E.; Riederer, P. (1995-07-01). "Noncompetitive NMDA Receptor Antagonists with Fast Open-Channel Blocking Kinetics and Strong Voltage-Dependency as Potential Therapeutic Agents for Alzheimer's Dementia". Pharmacopsychiatry. 28 (04): 113–124. doi:10.1055/s-2007-979603. ISSN 0176-3679.
  16. ^ a b Kocahan, Sayad; Doğan, Zumrut (2017-02-28). "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: The Official Scientific Journal of the Korean College of Neuropsychopharmacology. 15 (1): 1–8. doi:10.9758/cpn.2017.15.1.1. ISSN 1738-1088. PMC 5290713. PMID 28138104.
  17. ^ a b Lubamba, Bob; Dhooghe, Barbara; Noel, Sabrina; Leal, Teresinha (2012-10-01). "Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy". Clinical Biochemistry. 45 (15): 1132–1144. doi:10.1016/j.clinbiochem.2012.05.034. ISSN 1873-2933. PMID 22698459.
  18. ^ Schultz, B. D.; DeRoos, A. D.; Venglarik, C. J.; Singh, A. K.; Frizzell, R. A.; Bridges, R. J. (1996-08-01). "Glibenclamide blockade of CFTR chloride channels". The American Journal of Physiology. 271 (2 Pt 1): L192–200. ISSN 0002-9513. PMID 8770056.
  19. ^ Zhang, Z. R.; Zeltwanger, S.; McCarty, N. A. (2000-05-01). "Direct comparison of NPPB and DPC as probes of CFTR expressed in Xenopus oocytes". The Journal of Membrane Biology. 175 (1): 35–52. ISSN 0022-2631. PMID 10811966.
  20. ^ Linsdell, P; Hanrahan, J W (1996-11-01). "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): 687–693. ISSN 0022-3751. PMC 1160856. PMID 8930836.
  21. ^ Linsdell, Paul (2014-02-26). "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. ISSN 1949-8454. PMC 3942540. PMID 24600512.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ Ramos, Eugene; O'Leary, Michael E. (2004-10-01). "State-dependent trapping of flecainide in the cardiac sodium channel". The Journal of Physiology. 560 (1): 37–49. doi:10.1113/jphysiol.2004.065003. ISSN 1469-7793. PMC 1665201. PMID 15272045.
  23. ^ a b Frizzell, Raymond A.; Hanrahan, John W. (2017-03-27). "Physiology of Epithelial Chloride and Fluid Secretion". Cold Spring Harbor Perspectives in Medicine. 2 (6). doi:10.1101/cshperspect.a009563. ISSN 2157-1422. PMC 3367533. PMID 22675668.
  24. ^ Muanprasat, Chatchai; Sonawane, N.D.; Salinas, Danieli; Taddei, Alessandro; Galietta, Luis J.V.; Verkman, A.S. (2017-03-27). "Discovery of Glycine Hydrazide Pore-occluding CFTR Inhibitors". The Journal of General Physiology. 124 (2): 125–137. doi:10.1085/jgp.200409059. ISSN 0022-1295. PMC 2229623. PMID 15277574.
  25. ^ Ma, Tonghui; Thiagarajah, Jay R.; Yang, Hong; Sonawane, Nitin D.; Folli, Chiara; Galietta, Luis J.V.; Verkman, A.S. (2002-12-01). "Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin–induced intestinal fluid secretion". The Journal of Clinical Investigation. 110 (11): 1651–1658. doi:10.1172/JCI16112. ISSN 0021-9738. PMC 151633. PMID 12464670.
  26. ^ Chen, Hui; Ruan, Ye Chun; Xu, Wen Ming; Chen, Jing; Chan, Hsiao Chang (2012-11-01). "Regulation of male fertility by CFTR and implications in male infertility". Human Reproduction Update. 18 (6): 703–713. doi:10.1093/humupd/dms027. ISSN 1460-2369. PMID 22709980.
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