N-Terminal Domains in Mouse and Human 5-Hydroxytryptamine<sub>3A</sub> Receptors Confer Partial Agonist and Antagonist Properties to Benzylidene Analogs of Anabaseine

Zhang, Ran; White, Natalie A.; Soti, Ferenc; Kem, William R.; Machu, Tina K.

doi:10.1124/jpet.106.101485

Cited by 10 publications

(13 citation statements)

References 31 publications

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“…In addition to agonist ligands, allosteric modulators are also known to bind to the N-terminal domain of Cys-loop receptors, with the best known example being BZDs, which bind to the interface of ␣/␥ subunits of GABA A Rs (Sigel, 2002). Loops C and F have been reported to play a critical role in differential pharmacological actions of drugs on both 5-HT 3A and GABA A Rs (Zhang et al, 2006(Zhang et al, , 2007Padgett and Lummis, 2008). There are 16 differences between mouse and human receptors in the distal one third of the N terminus, seven in loop C, and nine in or within proximity of loop F. To explore the N terminus as the potential location for the colchicine binding site, we created mouse-human and human-mouse chimeric receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Numbering of the amino acids in the two receptors began with the initiating methionine. Primers were used to introduce SpeI and NarI, and selection pressure for the mutagenesis was performed as described previously by Zhang et al (2006). Chimeric cDNAs were confirmed by dideoxynucleotide sequencing at the Biotechnology Core Facility at Texas Tech University (Lubbock, TX).…”

Section: Methodsmentioning

confidence: 99%

“…Studies using nACh/5-HT3 receptor chimeras have shown that the ligand binding domains of the receptors are in the N terminus (Eiselé et al, 1993;Craig et al, 2004). To correlate species-differential colchicine actions to defined structural domains of 5-HT 3A Rs, we constructed four chimeric receptor cDNAs, as previously published (Zhang et al, 2006). The first chimera was designated H239M and contains the entire N-terminal domain of the human receptor cDNA and the balance of the mouse 5-HT 3A R cDNA.…”

Section: Colchicine Inhibits 5-ht-evoked Currents In X Laevismentioning

confidence: 99%

“…It is interesting that these small differences in amino acid composition are responsible for striking interspecies variation of responses to numerous drugs that act at the 5-HT recognition site, including curare (Miyake et al, 1995;Zhang et al, 2007), 2-methyl 5-HT (Maricq et al, 1991;Belelli et al, 1995), 1-phenylbiguanide (Maricq et al, 1991), and benzylidene analogs of anabasine (Zhang et al, 2006). Loops C and F have been implicated in interspecies differential potency of curare and m-clorophenylbiguanidine (Hope et al, 1999;Mochizuki et al, 1999;Zhang et al, 2007) and agonist function of 2-OHMBA (Zhang et al, 2006). The differential sensitivity of these drugs among interspecies 5-HT 3A Rs can be used to localize ligand binding domain(s) or gating residues through the use of interspecies chimeras and point mutations.…”

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Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine_3AReceptor

Oliveira-Pierce

Zhang

Machu

2009

J Pharmacol Exp Ther

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The actions of colchicine were examined with the two-electrode voltage-clamp technique and radioligand binding assays in mouse and human 5-hydroxytryptamine 3A receptors (5-HT 3A Rs) expressed in Xenopus laevis oocytes. Colchicine inhibited 5-hydroxytryptamine (5-HT)-evoked currents in oocytes expressing mouse 5-HT 3A Rs, with an IC 50 of 59.5 Ϯ 3 M. In contrast to the mouse receptor, coapplication of colchicine with 5-HT (Ͻ1 M) strongly enhanced 5-HT-evoked currents in oocytes expressing human 5-HT 3A Rs. Colchicine applied alone did not induce a detectable current. In the presence of 0.5 M 5-HT, the potentiation was concentration-dependent and reached the maximum (ϳ100%) when 750 M colchicine was applied. However, colchicine-dependent inhibition can be observed at 5-HT concentrations Ͼ 1 M. In oocyte membranes expressing mouse or human receptors, binding studies with colchicine, suggesting that actions of colchicine do not occur at the ligand binding domain. Functional effects of colchicine on both receptors occurred in the absence of preincubation and after cold temperature incubation, suggesting that the microtubule-depolymerizing effects of colchicine play no role in modulation of receptor function. Studies with interspecies chimeric receptors demonstrated that the distal one third of the N terminus is responsible for the bidirectional modulation by colchicine. Collectively, these results suggest that colchicine modulates receptor function through loops C and/or F through a gating mechanism.The 5-hydroxytryptamine 3 receptor (5-HT 3 R) belongs to the superfamily of ligand-gated ion channels (LGICs) (Maricq et al., 1991) and shares a number of structural and functional homologies with other members, such as the nicotinic acetylcholine receptor (nAChR), GABA receptor (GABA A R), and glycine receptor (GlyR) (Grenningloh et al., 1987;. To date, five 5-HT 3 receptor subunits have been cloned (A-E) (Maricq et al., 1991;Belelli et al., 1995;Niesler et al., 2007). Receptors composed of A-homomers and A/B-heteromers have been shown to have functional significance in the central and peripheral nervous systems (for review, see Thompson and Lummis, 2006), and a recent study reported expression of functional A/C-, A/D-, and A/E-heteromers (Niesler et al., 2007). The ligand binding domain (LBD) is located in the N terminus at the interface between subunits and consists of six loops, A to F. Loops A to C form the principal component of the LBD, and loops D to F form the complementary component of the LBD (for review, see Thompson and Lummis, 2006). Homology models using the acetylcholine-binding protein and biochemical studies have identified important residues for ligand binding on both the primary (loops A-C) and the complementary (loops D-F) interfaces of the binding site (Schreiter et al., 2003;Thompson et al., 2005).The homomeric 5-HT 3A R is a good model system for exploring the ligand recognition sites of LGICs. Significant homology exists between the 5-HT 3A Rs among the six cloned species (80 -95%). It is...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Colchicine Inhibits 5-ht-evoked Currents In X Laevismentioning

confidence: 99%

mentioning

confidence: 99%

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Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine_3AReceptor

Oliveira-Pierce

Zhang

Machu

2009

J Pharmacol Exp Ther

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“…In contrast, the agonist 2-methyl 5-HT has a greater efficacy at the human than mouse receptor (Werner et al, 1994; Miyake et al, 1995). Finally, 3-(2-hydroxy, 4-methoxybenzylidene)-anabaseine is a strong partial agonist at the mouse receptor and an apparent competitive antagonist at the human receptor (Zhang et al, 2006). …”

Section: Introduction To the 5-ht3 Receptor A Ligand-gated Ion Chmentioning

confidence: 99%

Therapeutics of 5-HT3 receptor antagonists: Current uses and future directions

Machu

2011

Pharmacology & Therapeutics

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The 5-Hydroxytryptamine3 (5-HT3) receptor is a member of the cys-loop family of ligand gated ion channels, of which the nicotinic acetylcholine receptor is the prototype. All other 5-HT receptors identified to date are metabotropic receptors. The 5-HT3 receptor is present in the central and peripheral nervous systems, as well as a number of non-nervous tissues. As an ion channel that is permeable to the cations, Na+, K+, and Ca2+, the 5-HT3 receptor mediates fast depolarizing responses in pre- and post-synaptic neurons. As such, 5-HT3 receptor antagonists that are used clinically block afferent and efferent synaptic transmission. The most well established physiological roles of the 5-HT3 receptor are to coordinate emesis and regulate gastrointestinal motility. Currently marketed 5-HT3 receptor antagonists are indicated for treatment of chemotherapy, radiation, and anesthesia-induced nausea and vomiting, as well as irritable bowel syndrome. Other therapeutic uses that have been explored include pain and drug addiction. The 5-HT3 receptor is one of a number of receptors that play a role in mediating nausea and vomiting, and as such, 5-HT3 receptor antagonists demonstrate greatest anti-emetic efficacy when administered in combination with other drug classes.

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Vagal‐α7 nicotinic acetylcholine receptor signaling exacerbates influenza severity by promoting lung epithelial cell infection

Zhao,

Pan,

Chen

et al. 2024

Journal of Medical Virology

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The vagus nerve circuit, operating through the alpha‐7 nicotinic acetylcholine receptor (α7 nAChR), regulates the inflammatory response by influencing immune cells. However, the role of vagal‐α7 nAChR signaling in influenza virus infection is unclear. In particular, does vagal‐α7 nAChR signaling impact the infection of alveolar epithelial cells (AECs), the primary target cells of influenza virus? Here, we demonstrated a distinct role of α7 nAChR in type II AECs compared to its role in immune cells during influenza infection. We found that deletion of Chrna7 (encoding gene of α7 nAChR) in type II AECs or disruption of vagal circuits reduced lung influenza infection and protected mice from influenza‐induced lung injury. We further unveiled that activation of α7 nAChR enhanced influenza infection through PTP1B‐NEDD4L‐ASK1‐p38MAPK pathway. Mechanistically, activation of α7 nAChR signaling decreased p38MAPK phosphorylation during infection, facilitating the nuclear export of influenza viral ribonucleoproteins and thereby promoting infection. Taken together, our findings reveal a mechanism mediated by vagal‐α7 nAChR signaling that promotes influenza viral infection and exacerbates disease severity. Targeting vagal‐α7 nAChR signaling may offer novel strategies for combating influenza virus infections.

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N-Terminal Domains in Mouse and Human 5-Hydroxytryptamine_3A Receptors Confer Partial Agonist and Antagonist Properties to Benzylidene Analogs of Anabaseine

Cited by 10 publications

References 31 publications

Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine_3AReceptor

Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine_3AReceptor

Therapeutics of 5-HT3 receptor antagonists: Current uses and future directions

Vagal‐α7 nicotinic acetylcholine receptor signaling exacerbates influenza severity by promoting lung epithelial cell infection

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N-Terminal Domains in Mouse and Human 5-Hydroxytryptamine3A Receptors Confer Partial Agonist and Antagonist Properties to Benzylidene Analogs of Anabaseine

Cited by 10 publications

References 31 publications

Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine3AReceptor

Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine3AReceptor

Therapeutics of 5-HT3 receptor antagonists: Current uses and future directions

Vagal‐α7 nicotinic acetylcholine receptor signaling exacerbates influenza severity by promoting lung epithelial cell infection

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Product

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N-Terminal Domains in Mouse and Human 5-Hydroxytryptamine_3A Receptors Confer Partial Agonist and Antagonist Properties to Benzylidene Analogs of Anabaseine

Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine_3AReceptor

Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine_3AReceptor