Pharmacological characterization of the apparent splice variants of the murine 5-HT3 R-A subunit expressed in Xenopus laevis oocytes

Downie, David L.; Hope, Anthony G.; Lambert, Jeremy J.; Peters, John A.; Blackburn, Thomas P.

doi:10.1016/0028-3908(94)90078-7

Cited by 52 publications

(61 citation statements)

References 22 publications

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“…In this respect the expression of both 5-HT3R-A and 5-HT3R-A, mRNA's in N1E-1 15 cells (Hope et al, 1993) is of particular interest. Previously we have found that, in the differentiated NIE-115 cells, the efficacy of 2-methyl-5-HT is approximately 75% of that of 5-HT (Kooyman et al, 1993a), suggesting the predominant expression of the 5-HT3R-A subunit (Downie et al, 1994). Moreover, all concentration-effect curves presented (Figures lb and 2) are monophasic and do not suggest the existence of receptor populations with distinct affinities.…”

Section: Dynamic Equilibria Between Receptor Statesmentioning

confidence: 66%

“…The selective 5-HT3 receptor agonist, 2-methyl-5-HT, which binds to 5-HT3 receptors in N1E-115 cells with similar affinity to 5-HT (Hoyer & Neijt, 1988), is also a partial agonist with an efficacy of 63% on 5-HT3R-A and of only 9% on 5-HT3R-As homopentameric receptors expressed in Xenopus oocytes (Downie et al, 1994). The agonists mCPBG and 5-HTQ are high-affinity receptor ligands and the former has been shown to act as a full 5-HT3 receptor agonist in NIE-115 cells.…”

Section: Introductionmentioning

confidence: 99%

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Selection of distinct conformational states of the 5‐HT₃ receptor by full and partial agonists

Hooft

Vijverberg

1996

British J Pharmacology

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2 The concentration-dependent activation and desensitization of the ion currents evoked by the agonists yield the potency order: mCPBG > 5-HTQ % 5-HT > > tryptamine > dopamine, and the efficacy order: 5-HT mCPBG 5-HTQ> > dopamine tryptamine. Thus, 5-HT, 5-HTQ and mCPBG are full agonists, whereas dopamine and tryptamine are partial agonists at the 5-HT3 receptor. 3 Full and partial agonists cause complete cross-desensitization and activate single channels with similar conductances and open lifetimes. This shows that full and partial agonists act on the same population of 5-HT3 receptors. 4 The time course of recovery from desensitization depends on the agonist used. Recovery from partial agonist-induced desensitization is single exponential, whereas the desensitization induced by full agonists recovers with sigmoid kinetics, suggesting at least 3 steps between 4 states. 5 During the process of recovery from cross-desensitization, the full agonists activate a larger fraction of the 5-HT3 receptors than the partial agonists, irrespective of the agonist used to induce desensitization. 6 It is concluded that full and partial agonists induce distinct desensitized states and, during recovery from desensitization, recognize distinct conformations of unoccupied 5-HT3 receptors. This conformational selection is likely to account for the different efficacies of full and partial 5-HT3, receptor agonists.

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Section: Dynamic Equilibria Between Receptor Statesmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Selection of distinct conformational states of the 5‐HT₃ receptor by full and partial agonists

Hooft

Vijverberg

1996

British J Pharmacology

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“…The 5-HT 3 R antisense probe protects 563 bases of the rat 5HT 3 R transcript between positions 268 and 831 of the rat cDNA sequence (Miyake et al, 1995). Both nodose and SCG neurons express two alternatively spliced 5-HT 3 R transcripts that encode receptor proteins that differ by five amino acids located between hydrophobic domains M3 and M4 at position 1153 (Miquel et al, 1995;Miyake et al, 1995); however, differences in the physiological role of the variants remain unclear (Downie et al, 1994). The probe we used detects both splice isoforms.…”

Section: Rnase Protection Assaysmentioning

confidence: 99%

Developing Neonatal Rat Sympathetic and Sensory Neurons Differ in Their Regulation of 5-HT₃Receptor Expression

1997

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Serotonin 5-HT 3 receptors (5-HT 3 Rs) are ligand-gated ion channels expressed by many peripheral neurons and are involved in several physiological processes. To learn more about the developmental regulation of 5-HT 3 R expression, we investigated rat sympathetic and vagal sensory neurons. We found that sympathetic and sensory neurons differ in their regulation of 5-HT 3 R expression during early postnatal life and as these neurons develop in culture. In SCG neurons 5-HT 3 R transcript levels are low at postnatal day 1 (P1) and increase 7.5-fold by P21; this increase occurs even after elimination of preganglionic innervation. In comparison, 5-HT 3 R mRNA levels in P1 nodose neurons are over 14-fold greater than in P1 SCG and change little by P21. We show that 5-HT 3 R transcript levels in nodose neurons depend on intact target innervation and drop by 60% after axotomy. When P1 SCG neurons develop in culture, we observed a significant increase in 5-HT 3 R expression: after 7 d in culture, transcript levels increase ninefold versus a threefold increase for neurons developing for 7 d in vivo. In contrast, 5-HT 3 R mRNA levels in cultured nodose neurons drop by 70% within 24 hr; however, this drop is transient. After 2 d, transcript levels begin to increase, and after 7 d, they are above initial values. We show that this delayed increase in 5-HT 3 R expression depends on neurotrophins. In both nodose and sympathetic neurons we found that the changes in 5-HT 3 R gene expression correlate directly with the appearance of 5-HTevoked current densities. Key words: 5-HT 3 receptor; ligand-gated ion channel; sympathetic; superior cervical ganglion; sensory; nodose; trigeminal; mRNA expression; neurotrophins; axotomyThe serotonin 5-HT 3 receptor (5-HT 3 R), a neurotransmittergated ion channel (Yakel and Jackson, 1988;Derkach et al., 1989;Maricq et al., 1991) present on many mammalian peripheral neurons, participates in several diverse physiological functions (Fozard, 1984;Jackson and Yakel, 1995). Activation of 5-HT 3 Rs located on peripheral vagal sensory nerve endings initiates reflexes affecting respiration, circulation, emesis, and swallowing (Douglas, 1975;Sanders-Bush and Mayer, 1996). 5-HT 3 Rs on spinal and vagal sensory neurons are involved in nociceptive signaling and nausea (Fozard, 1984). In the C NS 5-HT 3 Rs are implicated in anxiety, depression, and drug dependence (Apud, 1993;Greenshaw, 1993). In addition, 5-HT 3 Rs are expressed by sympathetic neurons; however, the role for these receptors in sympathetic f unction has not been f ully determined (Wallis and North, 1978;Yang et al., 1992).Many vagal afferent neurons expressing 5-HT 3 Rs are located in the nodose ganglion. These sensory neurons have typical unipolar polarities; their axons bif urcate into a peripheral branch that innervates much of the viscera, including heart, lungs, trachea, and gut, and a central branch that terminates mainly in the nucleus tractus solitarius (Andresen and Kunze, 1994). The physiological responses to serotonin elicited from ...

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“…Similar to other LGIC receptors, more than one subtype has been identified. Two splice variants of an A subunit (long and short forms), and a single B subunit have been cloned [10][11][12][13]. Both the long and short forms of the A subunit are capable of forming functional homomeric receptors [5-HT 3AL R and 5-HT 3AS R] although some differences between an agonist and partial agonist activity have been observed [14].…”

Section: Introductionmentioning

confidence: 99%

Untitled

et al. 2002

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Background: Lerisetron, a competitive serotonin type 3 receptor (5-HT 3 R) antagonist, contains five functional groups capable of interacting with amino acids in the 5-HT 3 R binding site. Site directed mutagenesis studies of the 5-HT 3A R have revealed several amino acids that are thought to form part of the binding domain of this receptor. The specific functional groups on the ligand that interact with these amino acids are, however, unknown. Using synthetic analogs of lerisetron as molecular probes in combination with site directed mutagenesis, we have identified some of these interactions and have proposed a model of the lerisetron binding site.

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Pharmacological characterization of the apparent splice variants of the murine 5-HT3 R-A subunit expressed in Xenopus laevis oocytes

Cited by 52 publications

References 22 publications

Selection of distinct conformational states of the 5‐HT₃ receptor by full and partial agonists

Selection of distinct conformational states of the 5‐HT₃ receptor by full and partial agonists

Developing Neonatal Rat Sympathetic and Sensory Neurons Differ in Their Regulation of 5-HT₃Receptor Expression

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Pharmacological characterization of the apparent splice variants of the murine 5-HT3 R-A subunit expressed in Xenopus laevis oocytes

Cited by 52 publications

References 22 publications

Selection of distinct conformational states of the 5‐HT3 receptor by full and partial agonists

Selection of distinct conformational states of the 5‐HT3 receptor by full and partial agonists

Developing Neonatal Rat Sympathetic and Sensory Neurons Differ in Their Regulation of 5-HT3Receptor Expression

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Selection of distinct conformational states of the 5‐HT₃ receptor by full and partial agonists

Selection of distinct conformational states of the 5‐HT₃ receptor by full and partial agonists

Developing Neonatal Rat Sympathetic and Sensory Neurons Differ in Their Regulation of 5-HT₃Receptor Expression