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The Journal of Neuroscience, November 28, 2007, 27(48):13151-13160; doi:10.1523/JNEUROSCI.3772-07.2007

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Cellular/Molecular
Differential Effects of Serotonin and Dopamine on Human 5-HT_3A Receptor Kinetics: Interpretation within an Allosteric Kinetic Model

Ken Solt,¹ Dirk Ruesch,^1,2 Stuart A. Forman,¹ Paul A. Davies,¹ and Douglas E. Raines¹

¹Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts 02114, and ²Department of Anesthesia and Critical Care, University Hospital Giessen-Marburg, Marburg Campus, 35033 Marburg, Germany

Correspondence should be addressed to Dr. Douglas E. Raines, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. Email: draines{at}partners.org

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-HT_3A 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-HT_3A 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.

Key words: serotonin; dopamine; receptor; kinetic; gating; channel

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Received Aug. 18, 2007; revised Oct. 10, 2007; accepted Oct. 15, 2007.

Correspondence should be addressed to Dr. Douglas E. Raines, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. Email: draines{at}partners.org

This article has been cited by other articles:

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				A. M. Dopico and D. M. Lovinger Acute Alcohol Action and Desensitization of Ligand-Gated Ion Channels Pharmacol. Rev., March 1, 2009; 61(1): 98 - 114. [Abstract] [Full Text] [PDF]

				C. Bouzat, M. Bartos, J. Corradi, and S. M. Sine The Interface between Extracellular and Transmembrane Domains of Homomeric Cys-Loop Receptors Governs Open-Channel Lifetime and Rate of Desensitization J. Neurosci., July 30, 2008; 28(31): 7808 - 7819. [Abstract] [Full Text] [PDF]

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