Coupling efficiency of brain β -adrenergic receptors to G s protein in suicide, alcoholism and control subjects

Abstract

Abnormal beta-adrenergic receptor (betaAR) density in the brains of suicide victims has been reported, although results of studies are inconsistent. Ethanol modifies betaAR-mediated signal transduction. Moreover abnormal betaAR function has been implicated in alcoholism. BetaAR antagonists, which were used as ligands in previous betaAR binding studies, also bind to 5-HT1B/1Dbeta receptors; hence, their estimates of betaAR density are confounded by binding to 5-HT1B/1Dbeta receptors. More importantly, previous studies did not examine betaAR agonist affinity or coupling efficiency to Gs protein. We investigated agonist affinity and coupling efficiency of betaAR to Gs protein in the brains of ten suicide victims, six subjects with alcoholism, and eight controls. There were no differences in betaAR density in either the frontal cortex or hippocampus of suicide victims or alcoholic subjects compared to controls. Preliminary results indicate betaAR supercoupling in suicide victims in both brain regions and uncoupling in alcoholic subjects in the frontal cortex. These results are discussed in view of the existing literature on the role of betaAR in suicide and alcoholism and the mechanism of action of antidepressants.

Monoamine Receptors and Signal Transduction Mechanisms in Suicide

“…The evidence that alterations in adrenergic receptors may be associated with suicidal behavior is primarily based on the observation that -adrenergic receptors were found to be decreased in the leukocytes of depressed patients by several investigators [146][147][148][149][150][151]. The observation that most of the antidepressant drugs on chronic treatment cause downregulation of -adrenergic receptors in rat brain [152][153][154] also raises the possibility of the involvement ofadrenergic receptors in depression.…”

“…G protein function has been studied in the postmortem brain of suicide victims by several investigators [175,[218][219][220][221][222][223][224]. Cowburn et al [218] studied AC activity and G i protein subunit levels in the frontal cortex obtained from 18 suicide victims and 22 matched control subjects.…”

“…Gurguis et al [221] determined the affinity and coupling efficiency of -adrenergic receptors to G S protein in the postmortem brain from 10 suicide victims and 6 subjects with alcoholism and 8 normal control subjects. They determined the G i/2 K H (i.e., agonist dissociation constant in high conformational state) to K L (i.e., agonist dissociation constant in low conformational state) ratio in these subjects and found that the ratio was high in suicide victims, suggesting super-coupling of the receptors to the G S protein, compared with control groups.…”

Heterotrimeric G Proteins: Insights into the Neurobiology of Mood Disorders

“…Such methodological deficits may have influenced the obtained results in several ways. The presence of small sample sizes [57], heterogeneous groups (suicide victims without a medical diagnosis) [36,62,75], or the establishment of retrospective (postmortem) diagnosis of mood disorders in suicide victims [36,57,122,186,187] may be the basis of certain scientific discrepancies. Thus, it has been recently reported that, opposite to schizophrenia, reaching an accurate diagnosis for mood disorders is difficult to determine using retrospective diagnosis [43].…”

The neurobiology of suicide - A Review of post-mortem studies

“…One study reported an increase in biding to beta-adrenergic receptors in the PFC and the TC of the suicide victims [110]. Gurguis et al [111] examined agonist affinity and coupling efficiency of beta-adrenergic receptors to Gs protein in the brains of ten suicide victims. They found no differences in the receptor densities in either the FC or HIP of suicide victims compared to controls, however, the preliminary results indicated beta-adrenergic receptors supercoupling in suicide victims in both brain regions.…”