Human fibroblasts as a relevant model to study signal transduction in affective disorders

Manier, D. Hal; Shelton, Richard C.; Ellis, Truitt C.; Peterson, Courtney M.; Eiring, A.; Sulser, Fridolin

doi:10.1016/s0165-0327(99)00190-1

Cited by 42 publications

(44 citation statements)

References 17 publications

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“…The aim of the current study was to probe for differences in the 5-HT 2A receptormediated signal transduction pathway, using an ex vivo fibroblast cell culture model system. Previous studies in our laboratory have demonstrated significant differences in the adenylyl cyclase signaling pathway in melancholic subtype of depression vs controls and depressives with the atypical subtype (Shelton et al, 1996(Shelton et al, , 1999Manier et al, 2000). Since these results were found only in a subset of depressives, the differences could be masked in the total depressive patient population, underscoring the value of diagnostic subclassification.…”

Section: Introductionmentioning

confidence: 67%

“…We therefore compared 5-HT 2A receptor-mediated signaling in cultured fibroblasts from melancholic subtype of depression vs controls and nonmelancholic depressives. Fibroblasts and neurons share many of the same receptors and intracellular signaling molecules (Manier et al, 2000), including the 5-HT 2A receptor-Gq-PLC-PKC-CREB pathway. Furthermore, fibroblasts are relatively simple to obtain and maintain in culture in a controlled, reproducible environment, thus eliminating potential differences in drug treatment, transmitter or hormone exposure, or agonal states.…”

Section: Introductionmentioning

confidence: 99%

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Decreased Serotonin 5-HT2A Receptor-Stimulated Phosphoinositide Signaling in Fibroblasts from Melancholic Depressed Patients

Akın

Manier

Sanders‐Bush

et al. 2004

Neuropsychopharmacol

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Abnormalities in serotonin (5-HT) receptors and 5-HT receptor-mediated signal transduction systems have been widely reported in mood disorders. This study was intended to evaluate 5-HT 2A receptor-coupled activation of phosphatidylinositol (PI) hydrolysis in subtypes of depression. Samples for fibroblast culture were obtained from patients with major depression with or without melancholia, and normal controls. Dose response curves were determined for 5-HT-induced PI hydrolysis. PI response was determined for bradykinin and l-a-lysophosphatidic acid (LPA), alternative Gq-coupled receptor agonists. [ 125 I]LSD binding for 5-HT 2A also was conducted. Finally, Western blot analysis was performed for phospholipase C b1 (PLC b1 ) and Ga q/11 proteins. The maximum PI response observed with 5-HT was significantly lower in melancholics but not nonmelancholic patients relative to controls. Activation of PI hydrolysis by bradykinin and LPA was not reduced in melancholic vs melancholics and controls; responses to both agonists actually were increased in the melancholic group. [ 125 I]LSD binding, PLC b1 , and Ga q/11 protein levels did not differ between groups. The data raise the possibility that the reduced 5-HT 2A receptor-induced PI hydrolysis is intrinsic to the receptor itself or its coupling to Gq protein, and is not related to altered availability of the 5-HT 2A receptor, Gq or PLC.

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Section: Introductionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Decreased Serotonin 5-HT2A Receptor-Stimulated Phosphoinositide Signaling in Fibroblasts from Melancholic Depressed Patients

Akın

Manier

Sanders‐Bush

et al. 2004

Neuropsychopharmacol

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“…Accordingly, we have used differential display (Liang and Pardee, 1992) to contrast gene expression patterns in cultured fibroblasts from patients with major depression with melancholia vs normal volunteers and nonmelancholic depressives. The samples from patients with melancholia had previously been shown to have reduced PKA activity and CREB phosphorylation; the nonmelancholics and normal volunteers all had PKA-CREB-P within the normal range previously reported (Shelton et al, 1999;Manier et al, 2000). A strength of differential display is that it is capable of detecting both known and novel genes and does not require an a priori hypothesis.…”

Section: Introductionmentioning

confidence: 91%

“…Human fibroblasts as non-neuronal tissue express genes encoding proteins involved in monoaminergic-G-protein-coupled transduction cascades similar to the expression in neuronal tissue, for example, beta adrenoreceptors, 5HT 2A receptors, and G-proteins. Using human fibroblasts, our group has demonstrated abnormalities in the beta adrenoceptor-cyclic AMP-mediated activation of protein kinase A (PKA) and phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB) in patients with major depression, melancholic subtype, relative to normal volunteers and nonmelancholic depressives (Shelton et al, , 1999Manier et al, 1996Manier et al, , 2000. These findings are similar to the results from other investigators, including a decrease in the putative binding of cyclic AMP to PKA in post-mortem brains of patients with bipolar disorder (Rahman et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of Pentraxin 3 in Fibroblasts from Patients with Major Depression

Shelton

Shan

Peng

et al. 2003

Neuropsychopharmacol

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In this study, differential display technology was used to compare gene expression in cultured fibroblasts from patients with major depression, melancholic subtype vs nonmelancholic depressives and normal volunteer controls. Genes differentially expressed in depressives and normals included an overexpressed 269 bp sequence tag showing B95% identity with the Homo sapiens long pentraxin 3 (PTX3) gene sequence in the 3 0 noncoding region. The 269 bp complimentary DNA probe hybridized with the 1.9 kb PTX3 mRNA. The densitometric analysis of slot blots showed that the mean steady-state mRNA level of PTX3 was 3.5-fold higher in the melancholic group as compared to that in normal controls and in nonmelancholic depressives (n ¼ 8, all groups). Incubation experiments were then conducted: confluent fibroblasts from melancholics and normal volunteers were incubated with isoproterenol 1 mM, dexamethasone (DEX) 500 nM, and interleukin 1b (IL-1b) 50 ng/ml, for 0, 0.5, 1, 4, and 24 h. mRNA was isolated and quantitated using Northern blot analysis. Isoproterenol produced no significant change in PTX3 expression; DEX produced a significant increase at 4 and 24 h; IL-1b induced an increase in both the groups that peaked at 4 h, declining to near basal levels at 24 h. There were no differences between melancholics or controls in mean change or maximum response with either DEX or IL-1b. The results are consistent with the reported effects of IL-1b on PTX3 expression in mouse brain. The results are of potential importance because PTX3 is a member of the long pentraxin subfamily of acute-phase proteins, which is inducible by IL-1b, and may play roles in neuroimmunity and neuroprotection.

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“…(26) For example, our research group has shown that, relative to normal controls, certain depressed patients have deficient PKA and PKC protein levels,(27;28) lower binding of cyclic AMP to PKA,(29) reduced phosphorylation of CREB, (29) and altered gene expression patterns; (30) (6;7;7;31-39) This decrease in the activity of these two key enzymes would be expected to alter the expression of genes that contain CRE elements in their promoters; these would include key proteins that regulate the stress response in brain, including brain derived neurotrophic factor (BDNF), (40)(41)(42)) the BDNF receptor trk-b, (43) and glucocorticoid receptors (GR). (44) Moreover, GR functions as a transcriptional factor and regulates the expression of other genes, specifically exerting an inhibitory effect on corticotrophin releasing hormone (CRH).…”

Section: Intracellular Signal Transductionmentioning

confidence: 99%

The Molecular Neurobiology of Depression

Shelton

2007

Psychiatric Clinics of North America

128

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The molecular neurobiology of depression begins with an idea: depressive disorders represent a family of related but distinct conditions. Different points of vulnerability in the brain may predispose to depressive disorders. For example, it is likely that the core pathophysiology of depression associated with early life adversity is different from non-trauma related disorders. In particular, the pathophysiology of trauma-related depression involves the hypothalamic-pituitary-adrenal (HPA) axis, although, in turn, this reflects underlying molecular etiologies. In particular, dysregulation of signal transduction mechanisms may be one site of origin. This may be the result of yet other processes such as the effects of reactive oxygen species (ROS) or genomic imprinting. Unraveling these complex causes may lead to novel treatments that can be used in a targeted fashion. Keywords/phrasesDepression; molecular; signal transduction; gene expression; genomics Unipolar depressive disorders encompass a range of features that strongly suggest a neurobiological substrate. These include symptoms such as include sleep and appetite disturbances (both up and down), loss of interest and pleasure, negative rumination, fatigue, and poor concentration, but also apparent abnormalities of the hypothalamic-pituitary-adrenal axis(1) or of neuroplasticity.(2) Moreover, depression appears to have genetic antecedents, which also point to a biological contribution to etiology.(3) However, the exact pathophysiology has been largely unknown until the last decade or so.To begin, depression clearly is not one entity, but subsumes a range of causes that involve genetic contributors, along with early and later stress.(2;4) Therefore, the depressive spectrum include conditions related to early traumatic events (typically with early onset of depression as well), through episodes in the absence of early trauma that may or may not be precipitated by an acute stressor. Therefore, the heterogeneous nature of the condition must be taken into account in any search for a biological substrate.Unfortunately, that is not usually the case. In fact, most studies simply take an unselected groups of "depressed" and "controls" for comparison. However, this is likely to contribute to type II error, since a particular biological finding may be applicable only to a subset of depressed patients. To illustrate this point, take a study from our own research laboratory ( Figure 1).(5) In this study, protein kinase A (PKA) activity was determined in fibroblasts in Mailing address: 1500 21st Avenue, South, Suite 2200, Nashville, TN 37212, Email: richard.shelton@vanderbilt.edu. Supported in part by NIMH grants MH073630, MH01741, and MH52339.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable fo...

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Human fibroblasts as a relevant model to study signal transduction in affective disorders

Cited by 42 publications

References 17 publications

Decreased Serotonin 5-HT2A Receptor-Stimulated Phosphoinositide Signaling in Fibroblasts from Melancholic Depressed Patients

Decreased Serotonin 5-HT2A Receptor-Stimulated Phosphoinositide Signaling in Fibroblasts from Melancholic Depressed Patients

Differential Expression of Pentraxin 3 in Fibroblasts from Patients with Major Depression

The Molecular Neurobiology of Depression

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