Mechanism of block by fluoxetine of 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells

Jin Sung Choi, Bok Hee Choi, Hye Sook Ahn, Myung Jun Kim, Duck Joo Rhie, Shin Hee Yoon, Do Sik Min, Yang Hyeok Jo, Myung Suk Kim, Ki Wug Sung, Sang June Hahn

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Abstract

The effect of fluoxetine (Prozac) on 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells was examined using the whole-cell patch-clamp technique. Fluoxetine produced a significant reduction of peak amplitude without altering the activation time course of 5-HT3-mediated currents. These effects were concentration-dependent, with an IC50 value of 4.15μM. No voltage dependence was evident in fluoxetine's block of 5-HT3-mediated currents over the entire voltage range tested. The extent of block by pre-application of fluoxetine was significantly greater than that by co-application. Fluoxetine also increased the apparent rate of current desensitization to 5-HT application. Using a first-order kinetics analysis, the open-channel blocking rate constants were 0.06μM-1s-1 (k+1, association rate constant) and 0.05s-1 (k-1, dissociation rate constant), with an apparent Kd (=k-1/k+1) of 0.83μM. This value is close to an IC50 of 1.11μM obtained from the reduction in τ, the time constant of desensitization. Intracellular application of fluoxetine for long durations had no effect on the amplitude or kinetics of 5-HT3-mediated currents. Similarly, norfluoxetine, the major metabolite of fluoxetine, reduced the peak current, and enhanced the rate of current desensitization in a concentration-dependent manner with an IC 50 of 2.66μM, indicating that norfluoxetine is more potent than fluoxetine in blocking 5-HT3-mediated currents. These results indicate that, at clinically relevant concentrations, fluoxetine and its metabolite, norfluoxetine, block 5-HT3-mediated currents in NCB-20 neuroblastoma cells.

Original languageEnglish
Pages (from-to)2125-2132
Number of pages8
JournalBiochemical Pharmacology
Volume66
Issue number11
DOIs
Publication statusPublished - 2003 Dec 1

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Fluoxetine
Neuroblastoma
Rate constants
Metabolites
Inhibitory Concentration 50
Kinetics
Clamping devices
Electric potential
Patch-Clamp Techniques
Serotonin
Chemical activation
Association reactions

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Choi, J. S., Choi, B. H., Ahn, H. S., Kim, M. J., Rhie, D. J., Yoon, S. H., ... Hahn, S. J. (2003). Mechanism of block by fluoxetine of 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells. Biochemical Pharmacology, 66(11), 2125-2132. https://doi.org/10.1016/j.bcp.2003.08.012
Choi, Jin Sung ; Choi, Bok Hee ; Ahn, Hye Sook ; Kim, Myung Jun ; Rhie, Duck Joo ; Yoon, Shin Hee ; Min, Do Sik ; Jo, Yang Hyeok ; Kim, Myung Suk ; Sung, Ki Wug ; Hahn, Sang June. / Mechanism of block by fluoxetine of 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells. In: Biochemical Pharmacology. 2003 ; Vol. 66, No. 11. pp. 2125-2132.
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abstract = "The effect of fluoxetine (Prozac) on 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells was examined using the whole-cell patch-clamp technique. Fluoxetine produced a significant reduction of peak amplitude without altering the activation time course of 5-HT3-mediated currents. These effects were concentration-dependent, with an IC50 value of 4.15μM. No voltage dependence was evident in fluoxetine's block of 5-HT3-mediated currents over the entire voltage range tested. The extent of block by pre-application of fluoxetine was significantly greater than that by co-application. Fluoxetine also increased the apparent rate of current desensitization to 5-HT application. Using a first-order kinetics analysis, the open-channel blocking rate constants were 0.06μM-1s-1 (k+1, association rate constant) and 0.05s-1 (k-1, dissociation rate constant), with an apparent Kd (=k-1/k+1) of 0.83μM. This value is close to an IC50 of 1.11μM obtained from the reduction in τ, the time constant of desensitization. Intracellular application of fluoxetine for long durations had no effect on the amplitude or kinetics of 5-HT3-mediated currents. Similarly, norfluoxetine, the major metabolite of fluoxetine, reduced the peak current, and enhanced the rate of current desensitization in a concentration-dependent manner with an IC 50 of 2.66μM, indicating that norfluoxetine is more potent than fluoxetine in blocking 5-HT3-mediated currents. These results indicate that, at clinically relevant concentrations, fluoxetine and its metabolite, norfluoxetine, block 5-HT3-mediated currents in NCB-20 neuroblastoma cells.",
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Choi, JS, Choi, BH, Ahn, HS, Kim, MJ, Rhie, DJ, Yoon, SH, Min, DS, Jo, YH, Kim, MS, Sung, KW & Hahn, SJ 2003, 'Mechanism of block by fluoxetine of 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells', Biochemical Pharmacology, vol. 66, no. 11, pp. 2125-2132. https://doi.org/10.1016/j.bcp.2003.08.012

Mechanism of block by fluoxetine of 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells. / Choi, Jin Sung; Choi, Bok Hee; Ahn, Hye Sook; Kim, Myung Jun; Rhie, Duck Joo; Yoon, Shin Hee; Min, Do Sik; Jo, Yang Hyeok; Kim, Myung Suk; Sung, Ki Wug; Hahn, Sang June.

In: Biochemical Pharmacology, Vol. 66, No. 11, 01.12.2003, p. 2125-2132.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mechanism of block by fluoxetine of 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells

AU - Choi, Jin Sung

AU - Choi, Bok Hee

AU - Ahn, Hye Sook

AU - Kim, Myung Jun

AU - Rhie, Duck Joo

AU - Yoon, Shin Hee

AU - Min, Do Sik

AU - Jo, Yang Hyeok

AU - Kim, Myung Suk

AU - Sung, Ki Wug

AU - Hahn, Sang June

PY - 2003/12/1

Y1 - 2003/12/1

N2 - The effect of fluoxetine (Prozac) on 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells was examined using the whole-cell patch-clamp technique. Fluoxetine produced a significant reduction of peak amplitude without altering the activation time course of 5-HT3-mediated currents. These effects were concentration-dependent, with an IC50 value of 4.15μM. No voltage dependence was evident in fluoxetine's block of 5-HT3-mediated currents over the entire voltage range tested. The extent of block by pre-application of fluoxetine was significantly greater than that by co-application. Fluoxetine also increased the apparent rate of current desensitization to 5-HT application. Using a first-order kinetics analysis, the open-channel blocking rate constants were 0.06μM-1s-1 (k+1, association rate constant) and 0.05s-1 (k-1, dissociation rate constant), with an apparent Kd (=k-1/k+1) of 0.83μM. This value is close to an IC50 of 1.11μM obtained from the reduction in τ, the time constant of desensitization. Intracellular application of fluoxetine for long durations had no effect on the amplitude or kinetics of 5-HT3-mediated currents. Similarly, norfluoxetine, the major metabolite of fluoxetine, reduced the peak current, and enhanced the rate of current desensitization in a concentration-dependent manner with an IC 50 of 2.66μM, indicating that norfluoxetine is more potent than fluoxetine in blocking 5-HT3-mediated currents. These results indicate that, at clinically relevant concentrations, fluoxetine and its metabolite, norfluoxetine, block 5-HT3-mediated currents in NCB-20 neuroblastoma cells.

AB - The effect of fluoxetine (Prozac) on 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells was examined using the whole-cell patch-clamp technique. Fluoxetine produced a significant reduction of peak amplitude without altering the activation time course of 5-HT3-mediated currents. These effects were concentration-dependent, with an IC50 value of 4.15μM. No voltage dependence was evident in fluoxetine's block of 5-HT3-mediated currents over the entire voltage range tested. The extent of block by pre-application of fluoxetine was significantly greater than that by co-application. Fluoxetine also increased the apparent rate of current desensitization to 5-HT application. Using a first-order kinetics analysis, the open-channel blocking rate constants were 0.06μM-1s-1 (k+1, association rate constant) and 0.05s-1 (k-1, dissociation rate constant), with an apparent Kd (=k-1/k+1) of 0.83μM. This value is close to an IC50 of 1.11μM obtained from the reduction in τ, the time constant of desensitization. Intracellular application of fluoxetine for long durations had no effect on the amplitude or kinetics of 5-HT3-mediated currents. Similarly, norfluoxetine, the major metabolite of fluoxetine, reduced the peak current, and enhanced the rate of current desensitization in a concentration-dependent manner with an IC 50 of 2.66μM, indicating that norfluoxetine is more potent than fluoxetine in blocking 5-HT3-mediated currents. These results indicate that, at clinically relevant concentrations, fluoxetine and its metabolite, norfluoxetine, block 5-HT3-mediated currents in NCB-20 neuroblastoma cells.

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