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Articles, Cellular/Molecular

Differential Effects of Serotonin and Dopamine on Human 5-HT3A Receptor Kinetics: Interpretation within an Allosteric Kinetic Model

Ken Solt, Dirk Ruesch, Stuart A. Forman, Paul A. Davies and Douglas E. Raines
Journal of Neuroscience 28 November 2007, 27 (48) 13151-13160; DOI: https://doi.org/10.1523/JNEUROSCI.3772-07.2007
Ken Solt
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Dirk Ruesch
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Stuart A. Forman
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Paul A. Davies
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Douglas E. Raines
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Abstract

Serotonin type 3 (5-HT3) receptors are members of the pentameric Cys-loop superfamily of receptors that modulate synaptic neurotransmission. In response to agonist binding and unbinding, members of this superfamily undergo a series of conformational transitions that define their functional properties. In this study, we report the results of electrophysiological studies using rapid solution exchange designed to characterize and compare the actions of the high-efficacy agonist serotonin and the low-efficacy agonist dopamine on human 5-HT3A receptors expressed in human embryonic kidney HEK293 cells. In the case of serotonin, receptor activation rates varied with agonist concentration, and deactivation occurred as a single-exponential process with a rate that was similar to the maximal rate of desensitization. Receptors recovered slowly from long desensitizing pulses of serotonin with a sigmoidal time course. In the case of dopamine, receptor activation rates were independent of agonist concentration, receptor deactivation occurred as a complex process that was significantly faster than the maximal rate of desensitization, and recovery from desensitization occurred more quickly than with 5-HT and its time course was not sigmoidal. We developed an allosteric kinetic model for 5-HT3A receptor activation, deactivation, desensitization, and resensitization. Interpretation of our results within the context of this model indicated that the distinct modulatory actions of serotonin versus dopamine are largely attributable to the vastly different rates with which these two agonists induce channel opening and dissociate from open and desensitized states.

  • serotonin
  • dopamine
  • receptor
  • kinetic
  • gating
  • channel
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The Journal of Neuroscience: 27 (48)
Journal of Neuroscience
Vol. 27, Issue 48
28 Nov 2007
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Differential Effects of Serotonin and Dopamine on Human 5-HT3A Receptor Kinetics: Interpretation within an Allosteric Kinetic Model
Ken Solt, Dirk Ruesch, Stuart A. Forman, Paul A. Davies, Douglas E. Raines
Journal of Neuroscience 28 November 2007, 27 (48) 13151-13160; DOI: 10.1523/JNEUROSCI.3772-07.2007

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Differential Effects of Serotonin and Dopamine on Human 5-HT3A Receptor Kinetics: Interpretation within an Allosteric Kinetic Model
Ken Solt, Dirk Ruesch, Stuart A. Forman, Paul A. Davies, Douglas E. Raines
Journal of Neuroscience 28 November 2007, 27 (48) 13151-13160; DOI: 10.1523/JNEUROSCI.3772-07.2007
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