Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain

Pacheco, Mary A.; Stockmeier, Craig A.; Meltzer, Herbert Y.; Overholser, James C.; Dilley, Ginny E.; Jope, Richard S.

doi:10.1016/0006-8993(96)00207-7

Cited by 117 publications

(93 citation statements)

References 25 publications

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“…Recent studies have also investigated the activity of the PLC/phosphoinositide (PI) second messenger system in mood disorders Jope et al, 1996;Shimon et al, 1997;Soares and Mallinger, 1997;Pandey et al, 2002a, b). Pacheco et al (1996) found that GTPgS-stimulated PI hydrolysis is significantly lower in the brains of depressed persons who committed suicide relative to a normal control group. They also reported slightly lower PI responses to agonists such as 5-HT and ATP.…”

Section: Introductionmentioning

confidence: 89%

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: 89%

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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“…An enhanced immunoreactivity of brain G ␣s -protein has been associated with bipolar disorders 27,29,69 and depression 28,30 but evidence of unaltered G ␣s -protein levels has also been obtained, 26 even by the same groups. 70 Potential changes in G ␣1/2 -and G ␣o -protein levels occurring in brain of subjects with mood disorders have also been considered.…”

Section: Molecular Psychiatrymentioning

confidence: 99%

“…25 In the last years, the immunodetection of G-proteins with specific antibodies has led to altered levels of the different G-protein subunits in the brain of subjects with mood disorders. 13,[26][27][28][29][30] Because the amount of G i -proteins and the density of mature ␣ 2 -adrenoceptors maintain an stoichiometric equilibrium, 23,[31][32][33] the debate persists as to whether the receptor or the G-protein have the greater role in the observed up-regulation of ␣ 2 -adrenoceptors in mood disorders.…”

Section: Introductionmentioning

confidence: 99%

Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of α2A-adrenoceptors

et al. 2002

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“…suicide victims and bipolar patients Pacheco et al 1996). PI signal transduction determined by serotonin (5HT)-, thrombin-, and NaF-stimulated IP formation has also been reported to be increased in platelets of depressed patients (Mikuni et al 1991;Karege et al 1996).…”

mentioning

confidence: 99%

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Pandey

Dwivedi

SridharaRao

et al. 2002

Neuropsychopharmacology

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Phospholipase C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide (PI) signaling system. To examine if the abnormalities observed in the PIdrolysis of the substrate, phosphatidyl inositol 4,5-bisphosphate (PIP 2 ), by the enzyme phospholipase C (PLC), resulting in the formation of two second messengers, inositol 1,4,5-trisphophate (IP 3 ) and diacylglycerol (DAG) (Berridge and Irvine 1989). IP 3 stimulates the release of intracellular calcium from the endoplasmic reticulum, and DAG stimulates the enzyme protein kinase C (PKC) (Nishizuka 1992), which is one of the major intracellular mediators of signals generated by the stimulation of cell surface receptors.Several studies indicate abnormalities of the PI signaling system in patients with unipolar or bipolar disorders. It has been reported that the hydrolysis of PIP 2 by several agonists, such as sodium fluoride (NaF) and GTP ␥ S, is altered in the postmortem brain of depressed Pacheco et al. 1996). PI signal transduction determined by serotonin (5HT)-, thrombin-, and NaF-stimulated IP formation has also been reported to be increased in platelets of depressed patients (Mikuni et al. 1991;Karege et al. 1996). These abnormalities may be related to abnormalities in receptors, such as 5HT 2A , 5HT 2C , muscarinic M 1 and M 2 , or ␣ 2 adrenergic receptors linked to the PI signaling system or to abnormal levels of substrates, such as PIP 2 , or to components of the signaling cascade, such as G-proteins, PKC, or PLC. Abnormalities in 5HT 2A (Pandey et al. 1995), ␣ 2 adrenergic receptors (Pandey et al. 1990), G-proteins (Garcia-Sevilla et al. 1997Karege et al. 1998;Gurguis et al. 1999), and levels of PIP 2 , a substrate for PI-PLC (Brown et al. 1993;Soares and Mallinger 1996;Soares et al. 1999), have been reported in platelets of unipolar and/or bipolar patients. PLC and PKC are two crucial components of the PI signaling system. Both PKC and PLC have been shown to be involved in a variety of physiological functions, such as synthesis, release, and reuptake of neurotransmitters, neuronal development, transcription, longterm potentiation (LTP), and behavioral responses (Nishizuka 1992). Although the role of PLC in affective disorders has not been fully investigated, some studies have shown abnormalities of PLC in depression and suicide Pandey et al. 1999). On the other hand, very few studies have examined the role of PKC in bipolar or unipolar disorders, although PKC has been implicated in the pathophysiology of bipolar disorders. For example, it has been reported that PKC activity as well as translocation of PKC from cytosol to membrane are increased in platelets of bipolar patients and that lithium treatment alters the activity of PKC in platelets (Friedman et al. 1993;Wang et al. 1999). Further evidence for the involvement of PKC in bipolar disorders is derived from observations that lithium exerts significant effects on PKC in a number of cell systems, including central nervous system (CNS) (Manji et al. 1993(Manji et al. , 1995Manji ...

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Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain

Cited by 117 publications

References 25 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

Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of α2A-adrenoceptors

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

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