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[(3)H]cAMP binding sites and protein kinase a activity in the prefrontal cortex of suicide victims
Yogesh Dwivedi1, Robert R Conley, Rosalinda C Roberts
1Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 60612, USA. ydwivedi@psych.uic.edu
Objective:
The cAMP-dependent enzyme protein kinase A phosphorylates intracellular proteins upon activation and thereby plays a major role in mediating various physiological functions in the brain. To examine the role of this enzyme in suicidal behavior, the authors examined the catalytic and regulatory activities of protein kinase A in the postmortem brain of suicide victims.
Method:
Brain tissues were collected from 17 suicide victims and 17 nonpsychiatric comparison subjects. Regulatory activity was determined by examining [(3)H]cAMP binding to protein kinase A, while catalytic activity was determined by enzymatic assay in the presence (total activity) and the absence (endogenous activity) of cAMP in the membrane and cytosol fractions of the prefrontal cortex.
Results:
The number (B(max)) of [(3)H]cAMP binding sites to protein kinase A was significantly lower in the suicide victims without any changes in affinity in either the membrane or cytosol fractions of the prefrontal cortex. Further, significantly less protein kinase A activity, both in the presence and the absence of cAMP, was seen in the membrane and cytosol fractions of the prefrontal cortex of suicide victims; however, the difference in total protein kinase A activity was much more pronounced.
Conclusions:
The results suggest that cAMP binding to the regulatory subunits of protein kinase A, as well as the phosphotransfer catalytic activity of protein kinase A, are lower in the prefrontal cortex of suicide victims than in nonpsychiatric comparison subjects, which may be of clinical relevance in the pathophysiology of suicidal behavior.
Insights
Protein kinase A (PKA) activity and cAMP binding were significantly lower in the prefrontal cortex of suicide victims. These findings suggest PKA dysfunction may contribute to suicidal behavior pathophysiology.
Area of Science:
- Neuroscience
- Biochemistry
Background:
- Protein kinase A (PKA) is a crucial enzyme in brain signaling, mediating various physiological functions through protein phosphorylation.
- Dysregulation of PKA has been implicated in neurological disorders, prompting investigation into its role in suicidal behavior.
Purpose of the Study:
- To investigate the role of protein kinase A (PKA) in suicidal behavior by examining its catalytic and regulatory activities in the postmortem brain of suicide victims.
- To compare PKA activity and cAMP binding in the prefrontal cortex of suicide victims versus non-psychiatric controls.
Main Methods:
- Postmortem brain tissues from 17 suicide victims and 17 controls were analyzed.
- Regulatory activity was assessed via [(3)H]cAMP binding to PKA.
- Catalytic activity was measured using enzymatic assays in membrane and cytosol fractions of the prefrontal cortex.
Main Results:
- Suicide victims showed significantly fewer [(3)H]cAMP binding sites (B(max)) for PKA in both membrane and cytosol fractions, without changes in affinity.
- Both total and endogenous PKA catalytic activity were significantly reduced in the prefrontal cortex of suicide victims compared to controls.
- The reduction in total PKA activity was more pronounced than the reduction in endogenous activity.
Conclusions:
- Reduced cAMP binding to PKA regulatory subunits and lower phosphotransfer catalytic activity were observed in the prefrontal cortex of suicide victims.
- These PKA alterations may be clinically relevant in understanding the pathophysiology of suicidal behavior.
- Further research is warranted to explore PKA as a potential therapeutic target for suicidal behavior.
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