TY - JOUR
T1 - Towards a quantitative representation of the cell signaling mechanisms of hallucinogens
T2 - Measurement and mathematical modeling of 5-HT1A and 5-HT2A receptor-mediated ERK1/2 activation
AU - Chang, Chiung wen
AU - Poteet, Ethan
AU - Schetz, John A.
AU - Gümüş, Zeynep H.
AU - Weinstein, Harel
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - Computational simulations of signaling pathways
KW - G protein coupled receptors
KW - MAPK phosphorylation cascade
KW - Receptors of hallucinogenic drugs of abuse
KW - Serotonin receptors
KW - Systems biology
UR - http://www.scopus.com/inward/record.url?scp=58049163876&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2008.07.049
DO - 10.1016/j.neuropharm.2008.07.049
M3 - Article
C2 - 18762202
AN - SCOPUS:58049163876
SN - 0028-3908
VL - 56
SP - 213
EP - 225
JO - Neuropharmacology
JF - Neuropharmacology
IS - SUPPL. 1
ER -