Protein kinase A in postmortem brain of depressed suicide victims: Altered expression of specific regulatory and catalytic subunits

Background: We recently reported reduced [H-3]cyclic adenosine monophosphate binding and catalytic activity of protein kinase A in prefrontal cortex of depressed suicide victims. Here we examined the molecular basis of these alterations and whether these findings can be replicated in another cohort. Methods. Prefrontal cortex from depressed suicide victims and nonpsychiatric controls were obtained from the Lenhossek Human Brain Program, Budapest and the Maryland Brain Collection Program. [H-3]cyclic adenosine monophosphate binding and protein kinase A activity were determined by radioligand binding and enzymatic assay, respectively. Expression of catalytic and regulatory subunits was determined by quantitative reverse transcription polymerase chain reaction and Western blot, respectively. Results: [H-3]cyclic adenosine monophosphate binding and total and endogenous protein kinase A activity were significantly decreased in membrane and cytosol fractions of prefrontal cortex of depressed suicide victims from the Budapest cohort, with a similar magnitude (33%- 40% reduction) as reported for the Maryland cohort. In both cohorts, selective reduction (36%- 41%) in mRNA and protein expression of the regulatory RIIbeta and the catalytic Cbeta was observed. Conclusions: Our results suggest abnormalities in [H-3]cyclic adenosine monophosphate binding and catalytic activity kinase A in brain of depressed suicide victims, which could be due to reduced expression of RIIbeta and Cbeta. These abnormalities in PKA may be critical in the pathophysiology of depression.