Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study
Abstract
:1. Introduction
2. Results
2.1. RT² Profiler™ PCR Array Mouse GPCR Signaling PathwayFinder
2.2. mRNA Expression Changes in the Prefrontal Cortex
2.3. Changes in the Levels of Selected Signaling Proteins
3. Discussion
3.1. Changes in Gene Expression after CLZ Administration
3.2. Effect of KET on the GPCRs Signaling Pathway
4. Materials and Methods
4.1. Animals
4.2. RNA and Protein Isolation
4.3. RT2 qPCR
4.4. Data Analysis of RT2 qPCR and RT-PCR
4.5. Western Blot
4.6. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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G-Protein Coupled Receptors (GPCRs) | |
---|---|
Metabotropic Glutamate and GABA-Like Receptors | Casr, mGLuR1, mGluR2, mGluR4, mGluR5, mGluR7 |
Rhodopsin-Like Receptors | Adora2a, Adrb1, Adrb2, Agt, Agtr1a, Agtr1b, Agtr2, Agtrap, Drd1, Drd2, Galr2, Lhcgr, Lpar1, Lpar2, Oprd1, Oprk1, Ptgdr, Rho, Tshr |
Secretin-Like Receptors | Adgrb1, Adora2a, Calcr, Calcrl, Crhr1, Crhr2, Gcgr, Sctr |
Other G-Protein Coupled Receptors (GPCRs) | Edn1, S1pr1, S1pr2, S1pr3 |
G-Protein Coupled Receptor Signaling Pathways | |
Dopamine Receptor Signaling | Drd1, Drd2, Oprd1 |
G-Protein and cAMP/ Protein Kinase A Signaling | Adcy5, Adora2a, Adrb1, Adrb2, Calcr, Calcrl, Ccl2 (MCP1), Col1a1, Crhr1, Crhr2, Cyp19a1, Drd1, Edn1, Galr2, Gcgr, Gnaq, Gnas, Grm2, Grm4, Il1r1, Il1r2, Lhcgr, Nos2 (iNos), Oprd1, Oprk1, Ptgs2 (Cox2), Rgs2, Tshr, Ucp1, Vegfa |
G-Protein and IP3/Phospholipase C Signaling | Agtr1a, Agtr1b, Calcrl, Casr, Edn1, Gnaq, Grm5, Lpar1, Lpar2, Pik3cg |
Metabotropic Glutamate Receptor Signaling | Grm1, Grm2, Grm4, Grm5, Grm7 |
Neuropeptide Signaling | Adgrb1, Oprd1 |
Adenosine Receptor Signaling | Adcy5, Adora2a |
Calcium Signaling | Ccl2 (MCP-1), Ccl4 (Mip-1b), Col1a1, Egr1, Elk4, Kcnh8 (Elk1), Ptgs2 (Cox2) |
PKC Signaling | Agtr2, Col1a1, Dusp14, Egr1, Fgf2 (bFGF), Fos, Il1r1, Il1r2, Jun, Junb, Mmp9, Myc, Nos2 (iNos), Prkca, Ptgs2 (Cox2), Rgs2, Serpine1 (Pai-1), Socs1 |
Tyrosine Kinase Signaling | Adrb2, Akt1, Ccl4 (Mip-1b), Ccn2, Pdpk1, Prkca, Rgs2, Socs1, Ywhaz |
Protein Serine/Threonine Kinase Signaling | Akt1, Cdkn1b (p27Kip1), Pdpk1, Ptgdr |
MAP Kinase Signaling | Adrb2, Agt, Fgf2 (bFGF), Grm1, Grm4, Prkca, Tnf, Ucp1 |
PI3 Kinase Signaling | Akt1, Bcl2, Bcl2l1 (Bcl-XL), Ccnd1, Cdkn1b (p27Kip1), Cflar (Casper), Pdpk1, Pik3cg, Ptgs2 (Cox2) |
Nitric Oxide/cGMP Signaling | Agtr2, Nos2 (iNos), Ptgs2 (Cox2), Tnf |
RHO Signaling | Ccn2, Cdkn1b (p27Kip1), Fos, Il1b, Ptgs2 (Cox2), Rho, Serpine1 (Pai-1) |
IκB Kinase/NFκB Cascade | Agt, Cflar (Casper), Icam1, Il1b, Il2, Max, Nos2 (iNos), Ptgs2 (Cox2), Tnf, Vcam1 |
JAK/STAT Signaling | Ccl2 (MCP-1), Cdkn1a (p21Cip1, Waf1), Socs1 |
Other G-Protein Coupled Receptor Signaling Genes | Arrb1, Arrb2, Ccne1, Ccne2 |
Assay ID | Gene Symbol | Description |
---|---|---|
Mm00438308_m1 | Crhr2 | Corticotropin-Releasing Hormone Receptor 2 |
Mm00438545_m1 | DRD2 | Dopamine Receptor 2 |
Mm02524224_s1 | Adrb2 | βeta-2 adrenergic receptor |
Mm00617540_m1 | Arrb1 | Arrestin βeta 1 |
Mm00520666_g1 | Arrb2 | Arrestin βeta 2 |
Mm00726392_s1 | Galr2 | Galanin Receptor 2 |
Mm00810219_m1 | mGluR1 | Metabotropic glutamate receptor 1 |
Mm01235831_m1 | mGluR2 | Metabotropic glutamate receptor 2 |
Mm00690332_m1 | mGluR5 | Metabotropic glutamate receptor 5 |
Mm03928990_g1 | Rn18s | 18S ribosomal RNA |
Mm99999915_g1 | GAPDH | Glyceraldehyde-3-phosphate dehydrogenase |
Gene Symbol | Interaction | KET | CLZ |
---|---|---|---|
βarrestin 1 | F(1,16) = 11.47; p < 0.01 ** | F(1,16) = 3.304; p = 0.087 | F(1,16) = 0.125; p = 0.727 |
βarrestin 2 | F(1,16) = 12.07; p < 0.01 ** | F(1,16) = 0.449; p = 0.512 | F(1,16) = 0.108; p = 0.746 |
Dopamine Receptor 2 (DRD2) | F(1,16) = 7.742; p < 0.05 | F(1,16) = 5.716; p < 0.05 | F(1,16) = 0.164; p = 0.690 |
Metabotropic glutamate receptor 1 (mGluR1) | F(1,16) = 1.141; p = 0.301 | F(1,16) = 2.835; p = 0.111 | F(1,16) = 5.041; p < 0.05 * |
Metabotropic glutamate receptor 2 (mGluR2) | F(1,16) = 1.759; p = 0.203 | F(1,16) = 0.013; p = 0.908 | F(1,16) = 0.013; p = 0.908 |
Metabotropic glutamate receptor 5 (mGluR5) | F(1,16) = 0.8424; p = 0.372 | F(1,16) = 2.615 p = 0.125 | F(1,16) = 15.47; p < 0.01 ** |
Galanin Receptor 2 | F(1,16) = 6.699; p < 0.05 | F(1,16) = 2.450 p = 0.137 | F(1,16) = 0.018; p = 0.892 |
βeta-2 adrenergic receptor | F(1,16) = 0.6512; p = 0.431 | F(1,16) = 0.366; p = 0.553 | F(1,16) = 0.026; p = 0.873 |
Crhr2 | F(1,16) = 1.016; p = 0.328 | F(1,16) = 0.002; p = 0.961 | F(1,16) = 0.201; p = 0.659 |
Gene Symbol | Interaction | KET | CLZ |
---|---|---|---|
βarrestin 1 | F(2,24) = 1.598; p = 0.223 | F(1,24) = 2.345; p = 0.138 | F(2,24) = 2.432; p = 0.109 |
βarrestin 2 | F(2,24) = 0.871; p = 0.431 | F(1,24) = 14.41; p < 0.001 *** | F(2,24) = 1.842; p = 0.180 |
Dopamine Receptor 2 (DRD2) | F(2,24) = 2.730; p = 0.085 | F(1,24) = 0.258; p = 0.616 | F(2,24) = 4.135; p = 0.023 |
Metabotropic glutamate receptor 1 (mGluR1) | F(2,24) = 0.352; p = 0.706 | F(1,24) = 0.772; p = 0.388 | F(2,24) = 0.363; p = 0.699 |
Metabotropic glutamate receptor 2 (mGluR2) | F(2,24) = 0.698; p = 0.507 | F(1,24) = 0.174; p = 0.679 | F(2,24) = 2.308; p = 0.121 |
Metabotropic glutamate receptor 5 (mGluR5) | F(2,24) = 0.232; p = 0.794 | F(1,24) = 2.770; p = 0.109 | F(2,24) = 3.045; p = 0.066 |
Galanin Receptor 2 | F(2,24) = 0.778; p = 0.470 | F(1,24) = 0.024; p = 0.877 | F(2,24) = 0.781; p = 0.469 |
βeta-2 adrenergic receptor | F(2,24) = 1.018; p = 0.376 | F(1,24) = 1.229; p = 0.278 | F(2,24) = 1.748; p = 0.195 |
Crhr2 | F(2,24) = 0.390; p = 0.681 | F(1,24) = 0.002; p = 0.960 | F(2,24) = 1.824; p = 0.183 |
Gene Symbol | Interaction | KET | HAL |
βarrestin 1 | F(1,16) = 3.912; p = 0.065 | F(1,16) = 0.423; p = 0.524 | F(1,16) = 0.097; p = 0.758 |
βarrestin 2 | F(1,16) = 10.800; p < 0.01 ** | F(1,16) = 3.856; p = 0.067 | F(1,16) = 2.764; p = 0.115 |
Dopamine Receptor 2 (DRD2) | F(1,16) = 6.586; p < 0.05 * | F(1,16) = 0.846; p = 0.371 | F(1,16) = 9.375; p < 0.01 ** |
Metabotropic glutamate receptor 1 (mGluR1) | F(1,16) = 0.676; p = 0.423 | F(1,16) = 1.289; p = 0.273 | F(1,16) = 0.005; p = 0.939 |
Metabotropic glutamate receptor 2 (mGluR2) | F(1,16) = 0.169; p = 0.674 | F(1,16) = 1.238; p = 0.282 | F(1,16) = 4.453; p = 0.051 |
Metabotropic glutamate receptor 5 (mGluR5) | F(1,16) = 3.583; p = 0.076 | F(1,16) = 0.714; p = 0.411 | F(1,16) = 0.0701; p = 0.795 |
Galanin Receptor 2 | F(1,16) = 1.508; p = 0.237 | F(1,16) = 2.089; p = 0.168 | F(1,16) = 0.397; p = 0.537 |
βeta-2 adrenergic receptor | F(1,16) = 0.131; p = 0.722 | F(1,16) = 4.120; p = 0.059 | F(1,16) = 4.758; p = 0.054 |
Crhr2 | F(1,16) = 0.196; p = 0.663 | F(1,16) = 0.069; p = 0.796 | F(1,16) = 2.714; p = 0.119 |
Protein Symbol | Interaction | KET | CLZ |
---|---|---|---|
βarrestin 1 | F(1,16) = 41.21; p < 0.001 *** | F(1,16) = 0.2384; p = 0.632 | F(1,16) = 0.918; p = 0.352 |
βarrestin 2 | F(1,16) = 0.024; p = 0.878 | F(1,16) = 0.048; p = 0.828 | F(1,16) = 17.87; p < 0.001 *** |
Grk2 | F(1,16) = 2.523; p = 0.132 | F(1,16) = 2.409; p = 0.140 | F(1,16) = 23.35; p < 0.01 ** |
Erk1/2 | F(1,16) = 0.261; p = 0.616 | F(1,16) = 12.480; p < 0.001 ** | F(1,16) = 2.825; p = 0.112 |
Girk 3 | F(1,16) = 2.750; p = 0.117 | F(1,16) = 36.42; p < 0.0001 *** | F(1,16) = 0.487; p = 0.495 |
Protein Symbol | Interaction | KET | CLZ |
βarrestin 1 | F(2,24) = 1.200; p = 0.318 | F(1,24) = 2.709; p = 0.112 | F(2,24) = 2. 654; p = 0.091 |
βarrestin 2 | F(2,24) = 0.172; p = 0.843 | F(1,24) = 0. 255; p = 0.618 | F(2,24) = 1.165; p = 0.329 |
Grk2 | F(2,24) = 1.471; p = 0.249 | F(1,24) = 5.516; p = 0.027 * | F(2,24) = 2.062; p = 0.149 |
Erk1/2 | F(2,24) = 1.061; p = 0.361 | F(1,24) = 0.126; p = 0.725 | F(2,24) = 0.721; p = 0.200 |
Girk 3 | F(2,24) = 1.900; p = 0.171 | F(1,24) = 0.586; p = 0.431 | F(2,24) = 0.871; p = 0.431 |
Protein Symbol | Interaction | KET | HAL |
βarrestin 1 | F(1,16) = 19.77; p = 0.0004 *** | F(1,16) = 1.183; p = 0.2928 | F(1,16) = 0.404; p = 0.533 |
βarrestin 2 | F(1,16) = 0.324; p = 0.577 | F(1,16) = 0.045; p = 0.833 | F(1,16) = 1.876; p = 0.189 |
Grk2 | F(1,16) = 6.290; p = 0.023 * | F(1,16) = 0.784; p = 0.389 | F(1,16) = 5.180; p = 0.037 * |
Erk1/2 | F(1,16) = 0.437; p = 0.518 | F(1,16) = 0.624; p = 0.441 | F(1,16) = 3.602; p = 0.076 |
Girk 3 | F(1,16) = 0.853; p = 0.369 | F(1,16) = 1.266; p = 0.277 | F(1,16) = 0.137; p = 0.740 |
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Korlatowicz, A.; Kuśmider, M.; Szlachta, M.; Pabian, P.; Solich, J.; Dziedzicka-Wasylewska, M.; Faron-Górecka, A. Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study. Int. J. Mol. Sci. 2021, 22, 12203. https://doi.org/10.3390/ijms222212203
Korlatowicz A, Kuśmider M, Szlachta M, Pabian P, Solich J, Dziedzicka-Wasylewska M, Faron-Górecka A. Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study. International Journal of Molecular Sciences. 2021; 22(22):12203. https://doi.org/10.3390/ijms222212203
Chicago/Turabian StyleKorlatowicz, Agata, Maciej Kuśmider, Marta Szlachta, Paulina Pabian, Joanna Solich, Marta Dziedzicka-Wasylewska, and Agata Faron-Górecka. 2021. "Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study" International Journal of Molecular Sciences 22, no. 22: 12203. https://doi.org/10.3390/ijms222212203