The Cys-loop ligand-gated ion channel superfamily includes receptors such as nicotinic acetylcholine, GABAA, glycine, and 5-HT3 receptors, composed of five protein subunits arranged pentamerically around a central pore. Named for a characteristic loop formed by conserved amino acids between two cysteine residues linked via a disulfide bond, these receptors are unique to eukaryotes within the larger family of pentameric ligand-gated ion channels. Each subunit has an extracellular N-terminal domain where neurotransmitters bind, four transmembrane alpha helices forming the pore predominantly by M2 helices, and an intracellular M3-M4 linker that connects to the cytoskeleton.
Binding
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 literature6 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.7 Upon interaction, the loop undergoes a conformational change and rotates down to cap the molecule in the binding site.
Channel gating
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.8
See also
- 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
References
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. https://pubmed.ncbi.nlm.nih.gov/2742850/ ↩
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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC549065 ↩
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. PMC 4795631. PMID 26986966. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795631 ↩
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. /wiki/Bibcode_(identifier) ↩
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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136689 ↩
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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136689 ↩
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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1276711 ↩
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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002373 ↩