ABSTRACT:
Chang2008 - ERK activation, hallucinogenic
drugs mediated signalling through serotonin receptors
This model is described in the article:
Towards a quantitative
representation of the cell signaling mechanisms of
hallucinogens: measurement and mathematical modeling of 5-HT1A
and 5-HT2A receptor-mediated ERK1/2 activation.
Chang CW, Poteet E, Schetz JA,
Gümü? ZH, Weinstein H.
Neuropharmacology 2009; 56 Suppl 1:
213-225
Abstract:
Through a multidisciplinary approach involving experimental
and computational studies, we address quantitative aspects of
signaling mechanisms triggered in the cell by the receptor
targets of hallucinogenic drugs, the serotonin 5-HT2A
receptors. To reveal the properties of the signaling pathways,
and the way in which responses elicited through these receptors
alone and in combination with other serotonin receptors'
subtypes (the 5-HT1AR), we developed a detailed mathematical
model of receptor-mediated ERK1/2 activation in cells
expressing the 5-HT1A and 5-HT2A subtypes individually, and
together. In parallel, we measured experimentally the
activation of ERK1/2 by the action of selective agonists on
these receptors expressed in HEK293 cells. We show here that
the 5-HT1AR agonist Xaliproden HCl elicited transient
activation of ERK1/2 by phosphorylation, whereas 5-HT2AR
activation by TCB-2 led to higher, and more sustained
responses. The 5-HT2AR response dominated the MAPK signaling
pathway when co-expressed with 5-HT1AR, and diminution of the
response by the 5-HT2AR antagonist Ketanserin could not be
rescued by the 5-HT1AR agonist. Computational simulations
produced qualitative results in good agreement with these
experimental data, and parameter optimization made this
agreement quantitative. In silico simulation experiments
suggest that the deletion of the positive regulators PKC in the
5-HT2AR pathway, or PLA2 in the combined 5-HT1A/2AR model
greatly decreased the basal level of active ERK1/2. Deletion of
negative regulators of MKP and PP2A in 5-HT1AR and 5-HT2AR
models was found to have even stronger effects. Under various
parameter sets, simulation results implied that the extent of
constitutive activity in a particular tissue and the specific
drug efficacy properties may determine the distinct dynamics of
the 5-HT receptor-mediated ERK1/2 activation pathways. Thus,
the mathematical models are useful exploratory tools in the
ongoing efforts to establish a mechanistic understanding and an
experimentally testable representation of hallucinogen-specific
signaling in the cellular machinery, and can be refined with
quantitative, function-related information.
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Chiung-wen Violet Chang 
