Attenuated 5‐HT_1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3‐kinase, Akt and mitogen‐activated protein kinase

Abstract

Positron emission tomography studies in major depression show reduced serotonin (5-HT) 1A receptor antagonist-binding potentials in many brain regions including occipital cortex. The functional meaning of this observation in terms of signal transduction is unknown. We used postmortem brain samples from depressed suicide victims to examine the downstream effectors of 5-HT 1A receptor activation. The diagnosis was established by means of psychological autopsy using Diagnostic and Statistical Manual of Mental Disorders (DSM) III-R criteria. Measurements of [ 35 S]GTPcS binding to Gai/o in the occipital cortex of suicide victims and matched controls revealed a blunted response in suicide subjects and a decrease in the coupling of 5-HT 1A receptor to adenylyl cyclase. No significant group differences were detected in the expression levels of Gai/o, Gaq/11 or Gas proteins, or in the activity of cAMP-dependent protein kinase A. Studies of a parallel transduction pathway downstream from 5-HT 1A receptor activation demonstrated a decrease in the activity of phosphatidylinositol 3-kinase and its downstream effector Akt, as well as an increase in PTEN (phosphatase and tensin homolog deleted on chromosome 10), the phosphatase that hydrolyzes phosphatidylinositol 3,4,5-triphosphate. Finally, the activation of extracellular signal-regulated kinases 1 and 2 was attenuated in suicide victims. These data suggest that the alterations in agonist-stimulated 5-HT 1A receptor activation in depressed suicide victims are also manifest downstream from the associated G protein, affecting the activity of second messengers in two 5-HT 1A receptor transduction pathways that may have implications for cell survival. Keywords: adenylyl cyclase, Akt, G protein, mitogen-activated protein kinase, phosphatidylinositol 3-kinase, suicide. J. Neurochem. (2003) 87, 182-194. Although several findings indicate that levels of the neurotransmitter serotonin (5-HT) are reduced in depressed suicide victims (Mann 1998), the physiological consequences of such a reduction for 5-HT-receptor-activated downstream signaling are less well described. Autoradiographic studies on brains obtained from suicide victims revealed an increased density of postsynaptic 5-HT 1A receptor agonist

Aberrant Extracellular Signal-Regulated Kinase (ERK) 5 Signaling in Hippocampus of Suicide Subjects

“…Interestingly, we found abnormalities in ERK-1/2 signaling in postmortem brain of these subjects, such that expression and activation of ERK-1/2 are decreased and expression of MAPK phosphatase1, involved in dephosphorylation and deactivation of ERK1/2, is increased (Dwivedi et al, 2001). Similar attenuation of ERK-1/2 activation has also been reported in postmortem brain of suicide subjects by Hsiung et al (2003). In addition, very recently, we reported that in ERK signaling, the upstream kinase B-Raf is less activated in postmortem brain of these subjects (Dwivedi et al, 2006).…”

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

“…Recently it was reported that PI 3-kinase activity is decreased in occipital cortex of suicide subjects (Hsiung et al, 2003) and that ECS (Altar et al, 2004) or long-term lithium treatment (Chalecka-Franaszek and Chuang, 1999) increases PI 3-kinase activity. Given the role of PI 3-kinase in a plethora of biological functions, these and our present findings appear to be quite significant and suggest the possibility that dysfunction of PI 3-kinase signaling may be important in the pathophysiologic mechanisms of suicide.…”

“…PI 3-Kinase Activity Assay P13-K activity was measured essentially by the procedure described by Hsiung et al (2003). Postmortem brain lysates (600 mg protein) were immunoprecipitated with an antibody directed against the p85 subunit and incubated on ice for 60 min.…”

“…Since many physiological functions, including prosurvival effects of neurotrophins, occur through the activation of PI 3-kinase (Yao and Cooper, 1995;Crowder and Freeman, 1998;Hetman et al, 1999;Liot et al, 2004), it is important to examine whether this signaling system is altered in postmortem brain of suicide subjects and therefore plays any role in the pathophysiologic mechanisms of suicide. A recent study indicates that the catalytic activity of PI 3-kinase is decreased in occipital cortex of suicide subjects (Hsiung et al, 2003), which suggests the possible involvement of PI 3-kinase in suicide. The present study was undertaken to comprehensively investigate PI 3-kinase signaling in postmortem brain of suicide subjects with and without a history of major depression.…”

Increased mRNA Expression of α2A-Adrenoceptors, Serotonin Receptors and μ-Opioid Receptors in the Brains of Suicide Victims

“…It has been suggested that impaired receptor sensitivity (Cowen et al, 1994) or altered signaling (Lesch et al, 1990) could account for the apparent decreases in receptor abundance, although post-transcriptional regulation and protein degradation (Young et al, 1987;Busquets et al, 1997;Ventayol et al, 1997) could also be involved in the differences observed between receptor mRNA and protein levels. In fact, a functional impairment of 5-HT 1A -associated signaling is originated by alteration of downstream transduction proteins in the brains of suicides (Hsiung et al, 2003). Moreover, a lower serotonergic activity associated with suicidal behavior has been also shown through positron emission tomography studies in depressed subjects and radioligand binding studies in post-mortem brain of suicides (Oquendo et al, 2003;Stockmeier et al, 1998).…”