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Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants.

Oved K, Morag A, Pasmanik-Chor M, Rehavi M, Shomron N, Gurwitz D - Transl Psychiatry (2013)

Bottom Line: We compared genome-wide expression profiles of human lymphoblastoid cell lines from unrelated individuals following treatment with 1 μM paroxetine for 21 days with untreated control cells and examined which genes and microRNAs (miRNAs) showed the most profound and consistent expression changes.Using genome-wide miRNA arrays, we observed a corresponding decrease in the expression of two miRNAs, miR-221 and miR-222, both predicted to target ITGB3.Further genes whose expression was significantly modulated by chronic paroxetine are also implicated in neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel [2] Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

ABSTRACT
Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depression. However, the link between inhibition of serotonin reuptake and remission from depression remains controversial: in spite of the rapid onset of serotonin reuptake inhibition, remission from depression takes several weeks, presumably reflecting synaptogenesis/neurogenesis and neuronal rewiring. We compared genome-wide expression profiles of human lymphoblastoid cell lines from unrelated individuals following treatment with 1 μM paroxetine for 21 days with untreated control cells and examined which genes and microRNAs (miRNAs) showed the most profound and consistent expression changes. ITGB3, coding for integrin beta-3, showed the most consistent altered expression (1.92-fold increase, P=7.5 × 10(-8)) following chronic paroxetine exposure. Using genome-wide miRNA arrays, we observed a corresponding decrease in the expression of two miRNAs, miR-221 and miR-222, both predicted to target ITGB3. ITGB3 is crucial for the activity of the serotonin transporter (SERT), the drug target of SSRIs. Moreover, it is presumably required for the neuronal guidance activity of CHL1, whose expression was formerly identified as a tentative SSRI response biomarker. Further genes whose expression was significantly modulated by chronic paroxetine are also implicated in neurogenesis. Surprisingly, the expression of SERT or serotonin receptors was not modified. Our findings implicate ITGB3 in the mode of action of SSRI antidepressants and provide a novel link between CHL1 and the SERT. Our observations suggest that SSRIs may relieve depression primarily by promoting neuronal synaptogenesis/neurogenesis rather than by modulating serotonin neurotransmission per se.

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Related in: MedlinePlus

Hypothetical model depicting the cell membrane proteins encoded by CHL1 andSLC6A4 (SERT) competing on a limited pool of integrin beta-3 (ITGB3) protein.(a) At low CHL1 expression levels, more ITGB3 is available for supportingserotonin transporter (SERT) serotonin-uptake activity, hence higher sensitivity to SSRIdrugs is observed. (b) At high CHL1 expression levels (and similar SERT and ITGB3expression levels as depicted in panel a) more ITGB3 interacts with CHL1 and lessITGB3 is available for supporting SERT serotonin-uptake activity, hence lowersensitivity to SSRI drugs is observed.
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fig3: Hypothetical model depicting the cell membrane proteins encoded by CHL1 andSLC6A4 (SERT) competing on a limited pool of integrin beta-3 (ITGB3) protein.(a) At low CHL1 expression levels, more ITGB3 is available for supportingserotonin transporter (SERT) serotonin-uptake activity, hence higher sensitivity to SSRIdrugs is observed. (b) At high CHL1 expression levels (and similar SERT and ITGB3expression levels as depicted in panel a) more ITGB3 interacts with CHL1 and lessITGB3 is available for supporting SERT serotonin-uptake activity, hence lowersensitivity to SSRI drugs is observed.

Mentions: We postulate a tentative working hypothesis (Figure 3) forthe involvement of ITGB3, whose expression was most consistently increased followingchronic paroxetine, in the mode of action of SSRIs and its relation to the previouslyreported role of CHL1 expression levels in modulating SSRI sensitivity ofLCLs.24 Our working hypothesis is builtupon the observation that the integrin beta-3 subunit encoded by ITGB3 isrequired for the activity of the SERT, the drug target of SSRIs, as evident from thedrastically reduced serotonin-uptake activity in ITGB3-knockoutmice.45 Notably, these mice exhibitabsence of preference for social novelty and increased grooming in novel environments,behaviors relevant for autism spectrum disorder.46 Neuroanatomical assessment of these mice indicated that many brainregions had significantly different relative volumes, including a smaller corpuscallosum volume and bilateral decreases in the hippocampus, striatum and cerebellum, allrelevant to autism.47 Together these findingssuggest that ITGB3 is crucial for correct neuroanatomical development of the brain, aproperty it shares with CHL1.29


Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants.

Oved K, Morag A, Pasmanik-Chor M, Rehavi M, Shomron N, Gurwitz D - Transl Psychiatry (2013)

Hypothetical model depicting the cell membrane proteins encoded by CHL1 andSLC6A4 (SERT) competing on a limited pool of integrin beta-3 (ITGB3) protein.(a) At low CHL1 expression levels, more ITGB3 is available for supportingserotonin transporter (SERT) serotonin-uptake activity, hence higher sensitivity to SSRIdrugs is observed. (b) At high CHL1 expression levels (and similar SERT and ITGB3expression levels as depicted in panel a) more ITGB3 interacts with CHL1 and lessITGB3 is available for supporting SERT serotonin-uptake activity, hence lowersensitivity to SSRI drugs is observed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818017&req=5

fig3: Hypothetical model depicting the cell membrane proteins encoded by CHL1 andSLC6A4 (SERT) competing on a limited pool of integrin beta-3 (ITGB3) protein.(a) At low CHL1 expression levels, more ITGB3 is available for supportingserotonin transporter (SERT) serotonin-uptake activity, hence higher sensitivity to SSRIdrugs is observed. (b) At high CHL1 expression levels (and similar SERT and ITGB3expression levels as depicted in panel a) more ITGB3 interacts with CHL1 and lessITGB3 is available for supporting SERT serotonin-uptake activity, hence lowersensitivity to SSRI drugs is observed.
Mentions: We postulate a tentative working hypothesis (Figure 3) forthe involvement of ITGB3, whose expression was most consistently increased followingchronic paroxetine, in the mode of action of SSRIs and its relation to the previouslyreported role of CHL1 expression levels in modulating SSRI sensitivity ofLCLs.24 Our working hypothesis is builtupon the observation that the integrin beta-3 subunit encoded by ITGB3 isrequired for the activity of the SERT, the drug target of SSRIs, as evident from thedrastically reduced serotonin-uptake activity in ITGB3-knockoutmice.45 Notably, these mice exhibitabsence of preference for social novelty and increased grooming in novel environments,behaviors relevant for autism spectrum disorder.46 Neuroanatomical assessment of these mice indicated that many brainregions had significantly different relative volumes, including a smaller corpuscallosum volume and bilateral decreases in the hippocampus, striatum and cerebellum, allrelevant to autism.47 Together these findingssuggest that ITGB3 is crucial for correct neuroanatomical development of the brain, aproperty it shares with CHL1.29

Bottom Line: We compared genome-wide expression profiles of human lymphoblastoid cell lines from unrelated individuals following treatment with 1 μM paroxetine for 21 days with untreated control cells and examined which genes and microRNAs (miRNAs) showed the most profound and consistent expression changes.Using genome-wide miRNA arrays, we observed a corresponding decrease in the expression of two miRNAs, miR-221 and miR-222, both predicted to target ITGB3.Further genes whose expression was significantly modulated by chronic paroxetine are also implicated in neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel [2] Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

ABSTRACT
Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depression. However, the link between inhibition of serotonin reuptake and remission from depression remains controversial: in spite of the rapid onset of serotonin reuptake inhibition, remission from depression takes several weeks, presumably reflecting synaptogenesis/neurogenesis and neuronal rewiring. We compared genome-wide expression profiles of human lymphoblastoid cell lines from unrelated individuals following treatment with 1 μM paroxetine for 21 days with untreated control cells and examined which genes and microRNAs (miRNAs) showed the most profound and consistent expression changes. ITGB3, coding for integrin beta-3, showed the most consistent altered expression (1.92-fold increase, P=7.5 × 10(-8)) following chronic paroxetine exposure. Using genome-wide miRNA arrays, we observed a corresponding decrease in the expression of two miRNAs, miR-221 and miR-222, both predicted to target ITGB3. ITGB3 is crucial for the activity of the serotonin transporter (SERT), the drug target of SSRIs. Moreover, it is presumably required for the neuronal guidance activity of CHL1, whose expression was formerly identified as a tentative SSRI response biomarker. Further genes whose expression was significantly modulated by chronic paroxetine are also implicated in neurogenesis. Surprisingly, the expression of SERT or serotonin receptors was not modified. Our findings implicate ITGB3 in the mode of action of SSRI antidepressants and provide a novel link between CHL1 and the SERT. Our observations suggest that SSRIs may relieve depression primarily by promoting neuronal synaptogenesis/neurogenesis rather than by modulating serotonin neurotransmission per se.

Show MeSH
Related in: MedlinePlus