5-HT3 Receptors in NG108-15 neuroblastoma × glioma cells: Effect of the novel agonist 1-(m-chlorophenyl)-biguanide

Boess, Frank; Sepúlveda, M.-I.; Lummis, Sarah C. R.; Martin, Ian L.

doi:10.1016/0028-3908(92)90188-u

Cited by 26 publications

(14 citation statements)

References 12 publications

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“…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. The apparent affinities of mCPBG and 5-HTQ obtained from radioligand binding experiments are much higher than those obtained from functional 5-HT3 receptor assays, in which these agonists are nearly equipotent to 5-HT (Richardson et al, 1985;Glennon et al, 1991;Sepilveda et al, 1991;Boess et al, 1992;Lummis et al, 1993).…”

Section: Introductionmentioning

confidence: 80%

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: Introductionmentioning

confidence: 80%

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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“…Several 5HT receptors have been identified (5HT 1 − 7 ) based on their structural, functional and pharmacological characteristics [35][36][37][38][39][40]. 5HT recptors are further divided into different subtypes, e.g.…”

Section: Introductionmentioning

confidence: 99%

The effect of serotonin and serotonin antagonists on bladder cancer cell proliferation

et al. 2006

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cancer tissue was determined by immunohistochemistry and Western blot analysis. RESULTS5HT caused a dose-dependent increase in the proliferation of HT1376 cells. The maximum increase in cell proliferation (12%; 12 samples, P < 0.001) was at 10 − 8 M as compared to the control at 72 h. At 10 − 4 M , 5HT 1A antagonist and 5HT 1B antagonist (SB224289 hydrochloride) had a 10% (12 samples, P < 0.001) and 93% (12, P < 0.001) inhibitory effect on HT1376 cell growth, respectively, compared to the control at 72 h. There was immunostaining for 5HT 1A and 5HT 1B receptors in HT1376 cells and malignant bladder tissue, confirming the presence of these two receptor subtypes. Western blot analysis showed the presence of 5HT 1A and 5HT 1B receptor proteins with bands of 46 kDa and 43 kDa, respectively. CONCLUSION5HT 1A and to a greater extent 5HT 1B antagonists significantly inhibit bladder cancer cell growth. This effect is probably mediated via the 5HT 1A and 5HT 1B receptors. These results highlight the potential use of 5HT 1A and 5HT 1B antagonists in the treatment of bladder cancer.

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“…Our previous studies showing differences in maximum responses caused by mCPBG (Sepulveda et al , 1991; Boess et al , 1992) can now be explained by different levels of splice variants rather than the presence of different subunits. Decreased levels of 5‐HT 3 ‐L mRNA upon differentiation have been observed for NG108–15 cells (Emerit et al , 1995), and these correlate with changes in response amplitude, half‐time of desensitization and voltage‐dependence of 5‐HT 3 responses (Shao et al , 1991).…”

Section: Discussionmentioning

confidence: 89%

“…Other 5‐HT 3 subunits cloned so far are all homologues of the 5‐HT 3 R‐A (also called 5‐HT 3 ‐L) subunit and include two derived from related cell lines: NG108–15 (Werner et al , 1994 and N1E‐115 mouse neuroblastoma (Hope et al , 1993), which exist as two splice variants, one of which is missing six amino acids in the M3–M4 intracellular loop (5‐HT 3 ‐RAs or 5‐HT 3 ‐S); interestingly only this latter version appears to exist in the human genome (Miyake et al , 1995). We have previously demonstrated a difference in agonist potency at 5‐HT 3 receptors in N1E‐115 cells as compared to those in NG108–15 cells (Sepulveda et al , 1991; Boess et al , 1992); m‐chlorophenylbiguanide (mCPBG) was a partial agonist in NG108–15 cells but a full agonist in N1E‐115 cells. This difference may be due to differential expression of the splice variants; developmental regulation of the two forms has been demonstrated in NG108–15 cells (Emerit et al , 1995).…”

Section: Introductionmentioning

confidence: 99%

Different efficacy of specific agonists at 5‐HT₃ receptor splice variants: the role of the extra six amino acid segment

Niemeyer

Lummis

1998

British J Pharmacology

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1 Whole cell voltage clamp electrophysiology and radioligand binding were used to examine the agonist characteristics of the two splice variants of the 5-HT 3 receptor which have been cloned from neuronal cell lines. Homo-oligomeric 5-HT 3 receptors were examined in HEK 293 cells stably transfected with either long (5-HT 3 -L) or short (5-HT 3 -S) receptor subunit DNAs. 2 Functional homo-oligomeric receptors were formed from both subunits, and responses to 5-HT 3 receptor agonists (5-hydroxytryptamine (5-HT), 2-methyl 5-HT and m-chlorophenylbiguanide) were qualitatively similar. 3 Maximum currents (R max ) elicited by the 5-HT 3 receptor agonists m-chlorophenylbiguanide (mCPBG) and 2-methyl-5-HT (2-Me-5-HT), as compared to 5-HT, di ered in the two splice variants: R max mCPBG/R max 5-HT values were 0.68+0.04 and 0.91+0.01 in 5-HT 3 -L and 5-HT 3 -S receptors, respectively. Comparable values for 2-Me-5-HT were 0.30+0.02 and 0.23+0.02. 4 Radioligand binding data showed no di erence in a nity of agonist or antagonist binding sites; thus the six amino acid deletion appears to cause di erences in agonist e cacy. 5 The role of the 6 amino acid insertion was further investigated by use of site-directed mutagenesis to create two mutant receptors, one where serine 286 was replaced with alanine, and the second where all 6 amino acids were replaced with alanines. 6 Examination of the mutant receptors when stably expressed in HEK 293 cells revealed agonist properties resembling long and not short 5-HT 3 receptors. Thus speci®c amino acids in this region are not responsible for the observed di erences. 7 The data show intracellular structure can have signi®cant e ects on ligand-gated ion channel function, and suggest that minor changes in structure may be responsible for di erences in function observed when ligand-gated ion channel proteins are modulated intracellularly.

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5-HT3 Receptors in NG108-15 neuroblastoma × glioma cells: Effect of the novel agonist 1-(m-chlorophenyl)-biguanide

Cited by 26 publications

References 12 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

The effect of serotonin and serotonin antagonists on bladder cancer cell proliferation

Different efficacy of specific agonists at 5‐HT₃ receptor splice variants: the role of the extra six amino acid segment

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5-HT3 Receptors in NG108-15 neuroblastoma × glioma cells: Effect of the novel agonist 1-(m-chlorophenyl)-biguanide

Cited by 26 publications

References 12 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

The effect of serotonin and serotonin antagonists on bladder cancer cell proliferation

Different efficacy of specific agonists at 5‐HT3 receptor splice variants: the role of the extra six amino acid segment

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Product

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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

Different efficacy of specific agonists at 5‐HT₃ receptor splice variants: the role of the extra six amino acid segment