ArticleThe Journal of biological chemistry2013
The minimum M3-M4 loop length of neurotransmitter-activated pentameric receptors is critical for the structural integrity of cytoplasmic portals.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 40 citations in OpenAlex.
- The serotonin-gated 5-HT3 receptor: a tale of functions and structures of a prototypical pentameric ligand-gated ion channel.Acta pharmacologica Sinica · 2026Review
- Structural basis of human zinc-activated channel (ZAC) signaling and modulation.Cell discovery · 2026Article
- Two residues determine nicotinic acetylcholine receptor requirement for RIC-3.Protein science : a publication of the Protein Society · 2023Article
- Binding motif for RIC-3 chaperon protein in serotonin type 3A receptors.The Journal of general physiology · 2023Article
- Reconstitution of an N-AChR from Brugia malayi, an evolved change in acetylcholine receptor accessory protein requirements in filarial parasites.PLoS pathogens · 2022Article
- Mobility of Lower MA-Helices for Ion Conduction through Lateral Portals in 5-HTBiophysical journal · 2020Article
- Thermodynamics and Kinetics of Ion Permeation in Wild-Type and Mutated Open Active Conformation of the Human α7 Nicotinic Receptor.Journal of chemical information and modeling · 2020Article
- Delineating the Site of Interaction of the 5-HTBiophysical journal · 2020Article
- Triple arginines as molecular determinants for pentameric assembly of the intracellular domain of 5-HTThe Journal of general physiology · 2019Article
- Amino acid substitutions in the human homomeric βThe Journal of biological chemistry · 2019Article
- A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Cryo-EM structure of 5-HTNature communications · 2018Article
- Loop G in the GABAThe Journal of physiology · 2017Article
- A role for loop G in the β1 strand in GABAA receptor activation.The Journal of physiology · 2016Article
- Direct interaction of the resistance to inhibitors of cholinesterase type 3 protein with the serotonin receptor type 3A intracellular domain.Journal of neurochemistry · 2016Article
- Pentameric quaternary structure of the intracellular domain of serotonin type 3A receptors.Scientific reports · 2016Article
- Functional Chimeras of GLIC Obtained by Adding the Intracellular Domain of Anion- and Cation-Conducting Cys-Loop Receptors.Biochemistry · 2015Article
- Article
- The role of intracellular linkers in gating and desensitization of human pentameric ligand-gated ion channels.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- Impact of intracellular domain flexibility upon properties of activated human 5-HT3 receptors.British journal of pharmacology · 2014Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The 5-HT3A receptor homology model, based on the partial structure of the nicotinic acetylcholine receptor from Torpedo marmorata, reveals an asymmetric ion channel with five portals framed by adjacent helical amphipathic (HA) stretches within the 114-residue loop between the M3 and M4 membrane-spanning domains. The positive charge of Arg-436, located within the HA stretch, is a rate-limiting determinant of single channel conductance (γ). Further analysis reveals that positive charge and volume of residue 436 are determinants of 5-HT3A receptor inward rectification, exposing an additional role for portals. A structurally unresolved stretch of 85 residues constitutes the bulk of the M3-M4 loop, leaving a >45-Å gap in the model between M3 and the HA stretch. There are no additional structural data for this loop, which is vestigial in bacterial pentameric ligand-gated ion channels and was largely removed for crystallization of the Caenorhabditis elegans glutamate-activated pentameric ligand-gated ion channels. We created 5-HT3A subunit loop truncation mutants, in which sequences framing the putative portals were retained, to determine the minimum number of residues required to maintain their functional integrity. Truncation to between 90 and 75 amino acids produced 5-HT3A receptors with unaltered rectification. Truncation to 70 residues abolished rectification and increased γ. These findings reveal a critical M3-M4 loop length required for functions attributable to cytoplasmic portals. Examination of all 44 subunits of the human neurotransmitter-activated Cys-loop receptors reveals that, despite considerable variability in their sequences and lengths, all M3-M4 loops exceed 70 residues, suggesting a fundamental requirement for portal integrity.
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