The Cys-loop ligand-gated ion channel superfamily is composed of nicotinic acetylcholine, GABAA, GABAA-ρ, glycine, 5-HT3, and zinc-activated (ZAC) receptors. These receptors are composed of five protein subunits which form a pentameric arrangement around a central pore. There are usually 2 alpha subunits and 3 other beta, gamma, or delta subunits (some consist of 5 alpha subunits). The name of the family refers to a characteristic loop formed by 13 highly conserved amino acids between two cysteine (Cys) residues, which form a disulfide bond[1] near the N-terminal extracellular domain.
Cys-loop receptors are known only in eukaryotes, but are part of a larger family of pentameric ligand-gated ion channels. Only the Cys-loop clade includes the pair of bridging cysteine residues.[2] The larger superfamily includes bacterial (e.g. GLIC) as well as non-Cys-loop eukaryotic receptors, and is referred to as "pentameric ligand-gated ion channels", or "Pro-loop receptors".[3]
All subunits consist of a large conserved extracellular N-terminal domain, three highly conserved transmembrane domains, a cytoplasmic loop of variable size and amino acid sequence, and a fourth transmembrane region with a relatively short and variable extracellular C-terminal domain. Neurotransmitters bind at the interface between subunits in the extracellular domain.
Each subunit contains four membrane-spanning alpha helices (M1, M2, M3, M4). The pore is formed primarily by the M2 helices.[4] The M3-M4 linker is the intracellular domain that binds the cytoskeleton.
Most knowledge about cys-loop receptors comes from inferences made while studying various members of the family. Research on the structures of acetylcholine binding proteins (AChBP) determined that the binding sites consist of six loops, with the first three forming the principal face and the next three forming the complementary face. The last loop on the principal face wraps over the ligand in the active receptor. This site is also abundant in aromatic residues.[5]
Recent literature[5] indicates that the Trp residue on loop B is crucial for both agonist and antagonist binding. The neurotransmitter is taken into the binding site where it interacts (through hydrogen and cation-π bonding) with the amino acid resides in the aromatic box, located on the principal face of the binding site. Another essential interaction occurs between the agonist and a tyrosine on loop C.[6] Upon interaction, the loop undergoes a conformational change and rotates down to cap the molecule in the binding site.
Image of nicotinic acetylcholine receptor - the most commonly studied member of the Cys-Loop receptor superfamily
Channel gatingedit
Through research done on nicotinic acetylcholine receptors it has been determined that the channels are activated through allosteric interactions between the binding and gating domains. Once the agonist binds it brings about conformational changes (including moving a beta sheet of the amino-terminal domain, and outward movement from loops 2, F and cys-loop which are tied to the M2-M3 linker and pull the channel open). Electron microscopy (at 9 Å) shows that the opening is caused by rotation at the M2 domain, but other studies on crystal structures of these receptors has shown that the opening could be a result from a M2 tilt which leads to pore dilation and a quaternary turn of the entire pentameric receptor.[7]
^Kellaris, Kennan Vincent (Apr 18, 1989). "Assessment of the number of free cysteines and isolation and identification of cystine-containing peptides from acetylcholine receptor". Biochemistry. 28 (8): 3469–3482. doi:10.1021/bi00434a048. PMID 2742850. Retrieved 3 February 2021.
^Tasneem A, Iyer L, Jakobsson E, Aravind L (2004). "Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels". Genome Biology. 6 (1): R4. doi:10.1186/gb-2004-6-1-r4. PMC549065. PMID 15642096.
^Jaiteh M, Taly A, Hénin J (2016). "Evolution of Pentameric Ligand-Gated Ion Channels: Pro-Loop Receptors". PLOS ONE. 11 (3): e0151934. Bibcode:2016PLoSO..1151934J. doi:10.1371/journal.pone.0151934. PMC4795631. PMID 26986966.
^Sine S; Engel A (2006). "Recent advances in Cys-loop receptor structure and function". Nature. 440 (7083): 448–55. Bibcode:2006Natur.440..448S. doi:10.1038/nature04708. PMID 16554804. S2CID 3899722.
^ abVan Arnam, EB; Dougherty, DA (August 14, 2014). "Functional probes of drug-receptor interactions implicated by structural studies: cys-loop receptors provide a fertile testing ground". Journal of Medicinal Chemistry. 57 (15): 6289–6300. doi:10.1021/jm500023m. PMC4136689. PMID 24568098.
^Bourne, Y; et al. (October 19, 2005). "Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations". The EMBO Journal. 24 (20): 3635–3646. doi:10.1038/sj.emboj.7600828. PMC1276711. PMID 16193063.
Yakel, J (February 15, 2010). "Advances and hold-ups in the study of structure, function and regulation of cys-loop ligand-gated ion channels and receptors". The Journal of Physiology. 588 (588 (Pt. 4)): 555–556. doi:10.1113/jphysiol.2009.185488. PMC2828129. PMID 20173078.
Pless, SA; Lynagh, T (April 24, 2014). "Principles of agonist recognition in Cys-loop receptors". Frontiers in Physiology. 5: 160. doi:10.3389/fphys.2014.00160. PMC4006026. PMID 24795655.
Albuquerque, EX; et al. (2009). "Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function". Physiol Rev. 89 (1): 73–120. doi:10.1152/physrev.00015.2008. PMC2713585. PMID 19126755.
External linksedit
April 13, 2024
loop, receptor, loop, ligand, gated, channel, superfamily, composed, nicotinic, acetylcholine, gabaa, gabaa, glycine, zinc, activated, receptors, these, receptors, composed, five, protein, subunits, which, form, pentameric, arrangement, around, central, pore, . The Cys loop ligand gated ion channel superfamily is composed of nicotinic acetylcholine GABAA GABAA r glycine 5 HT3 and zinc activated ZAC receptors These receptors are composed of five protein subunits which form a pentameric arrangement around a central pore There are usually 2 alpha subunits and 3 other beta gamma or delta subunits some consist of 5 alpha subunits The name of the family refers to a characteristic loop formed by 13 highly conserved amino acids between two cysteine Cys residues which form a disulfide bond 1 near the N terminal extracellular domain Cys loop receptors are known only in eukaryotes but are part of a larger family of pentameric ligand gated ion channels Only the Cys loop clade includes the pair of bridging cysteine residues 2 The larger superfamily includes bacterial e g GLIC as well as non Cys loop eukaryotic receptors and is referred to as pentameric ligand gated ion channels or Pro loop receptors 3 All subunits consist of a large conserved extracellular N terminal domain three highly conserved transmembrane domains a cytoplasmic loop of variable size and amino acid sequence and a fourth transmembrane region with a relatively short and variable extracellular C terminal domain Neurotransmitters bind at the interface between subunits in the extracellular domain Each subunit contains four membrane spanning alpha helices M1 M2 M3 M4 The pore is formed primarily by the M2 helices 4 The M3 M4 linker is the intracellular domain that binds the cytoskeleton Contents 1 Binding 2 Channel gating 3 See also 4 References 5 External linksBinding editMost knowledge about cys loop receptors comes from inferences made while studying various members of the family Research on the structures of acetylcholine binding proteins AChBP determined that the binding sites consist of six loops with the first three forming the principal face and the next three forming the complementary face The last loop on the principal face wraps over the ligand in the active receptor This site is also abundant in aromatic residues 5 Recent literature 5 indicates that the Trp residue on loop B is crucial for both agonist and antagonist binding The neurotransmitter is taken into the binding site where it interacts through hydrogen and cation p bonding with the amino acid resides in the aromatic box located on the principal face of the binding site Another essential interaction occurs between the agonist and a tyrosine on loop C 6 Upon interaction the loop undergoes a conformational change and rotates down to cap the molecule in the binding site nbsp Image of nicotinic acetylcholine receptor the most commonly studied member of the Cys Loop receptor superfamilyChannel gating editThrough research done on nicotinic acetylcholine receptors it has been determined that the channels are activated through allosteric interactions between the binding and gating domains Once the agonist binds it brings about conformational changes including moving a beta sheet of the amino terminal domain and outward movement from loops 2 F and cys loop which are tied to the M2 M3 linker and pull the channel open Electron microscopy at 9 A shows that the opening is caused by rotation at the M2 domain but other studies on crystal structures of these receptors has shown that the opening could be a result from a M2 tilt which leads to pore dilation and a quaternary turn of the entire pentameric receptor 7 See also editIon channel Nicotinic agonists Receptor biochemistry References edit Kellaris Kennan Vincent Apr 18 1989 Assessment of the number of free cysteines and isolation and identification of cystine containing peptides from acetylcholine receptor Biochemistry 28 8 3469 3482 doi 10 1021 bi00434a048 PMID 2742850 Retrieved 3 February 2021 Tasneem A Iyer L Jakobsson E Aravind L 2004 Identification of the prokaryotic ligand gated ion channels and their implications for the mechanisms and origins of animal Cys loop ion channels Genome Biology 6 1 R4 doi 10 1186 gb 2004 6 1 r4 PMC 549065 PMID 15642096 Jaiteh M Taly A Henin J 2016 Evolution of Pentameric Ligand Gated Ion Channels Pro Loop Receptors PLOS ONE 11 3 e0151934 Bibcode 2016PLoSO 1151934J doi 10 1371 journal pone 0151934 PMC 4795631 PMID 26986966 Sine S Engel A 2006 Recent advances in Cys loop receptor structure and function Nature 440 7083 448 55 Bibcode 2006Natur 440 448S doi 10 1038 nature04708 PMID 16554804 S2CID 3899722 a b Van Arnam EB Dougherty DA August 14 2014 Functional probes of drug receptor interactions implicated by structural studies cys loop receptors provide a fertile testing ground Journal of Medicinal Chemistry 57 15 6289 6300 doi 10 1021 jm500023m PMC 4136689 PMID 24568098 Bourne Y et al October 19 2005 Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations The EMBO Journal 24 20 3635 3646 doi 10 1038 sj emboj 7600828 PMC 1276711 PMID 16193063 Huang Y Zhang JL Wu W Chang YC June 2009 Allosteric activation mechanism of the cys loop receptors Acta Pharmacologica Sinica 30 6 663 672 doi 10 1038 aps 2009 51 PMC 4002373 PMID 19444220 Yakel J February 15 2010 Advances and hold ups in the study of structure function and regulation of cys loop ligand gated ion channels and receptors The Journal of Physiology 588 588 Pt 4 555 556 doi 10 1113 jphysiol 2009 185488 PMC 2828129 PMID 20173078 Pless SA Lynagh T April 24 2014 Principles of agonist recognition in Cys loop receptors Frontiers in Physiology 5 160 doi 10 3389 fphys 2014 00160 PMC 4006026 PMID 24795655 Albuquerque EX et al 2009 Mammalian Nicotinic Acetylcholine Receptors From Structure to Function Physiol Rev 89 1 73 120 doi 10 1152 physrev 00015 2008 PMC 2713585 PMID 19126755 External links editCys Loop Ligand Gated Channels Retrieved from https en wikipedia org w index php title Cys loop receptor amp oldid 1187424957, wikipedia, wiki, book, books, library,
