Protein kinases A and C in post-mortem prefrontal cortex from persons with major depression and normal controls

Abstract

Major depression (MDD) is a common and potentially life-threatening condition. Widespread neurobiological abnormalities suggest abnormalities in fundamental cellular mechanisms as possible physiological mediators. Cyclic AMP-dependent protein kinase (also known as protein kinase A [PKA]) and protein kinase C (PKC) are important components of intracellular signal transduction cascades that are linked to g-coupled receptors. Previous research using both human peripheral and post-mortem brain tissue specimens suggests that a subset of depressed patients exhibit reduced PKA and PKC activity, which has been associated with reduced levels of specific protein isoforms. Prior research also suggests that specific clinical phenotypes, particularly melancholia and suicide, may be particularly associated with low activity. This study examined PKA and PKC protein levels in human post-mortem brain tissue samples from persons with MDD (n=20) and age- and sex-matched controls (n=20). Specific PKA subunit and PKC isoforms were assessed using Western blot analysis in post-mortem samples from Brodmann area 10, which has been implicated in reinforcement and reward mechanisms. The MDD sample exhibited significantly lower protein expression of PKA regulatory Iα (RIα), PKA catalytic α (Cα) and Cβ, PKCβ1, and PKCε relative to controls. The melancholic subgroup showed low PKA RIα and PKA Cβ, while the portion of the MDD sample who died by suicide had low PKA RIα and PKA Cα. These data continue to support the significance of abnormalities of these two key kinases, and suggest linkages between molecular endophenotypes and specific clinical phenotypes.

Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior

“…cAMP/PKA signal transduction pathways have also been shown to be reduced in postmortem brain tissue from depressed patients (Shelton et al, 2009). …”

Participation of Antidiuretic Hormone (ADH) in Asthma Exacerbations Induced by Psychological Stress via PKA/PKC Signal Pathway in Airway-Related Vagal Preganglionic Neurons (AVPNs)

“…1 has revealed massively increased ADH and ADHR in Asthma + PS group, considering that the well-known ADHR subtypes (V1A, V1B, and V2) are members of the seven transmembrane domain G-protein-coupled receptor superfamily [34], and PKA/PKC are involved in cell signaling pathways linked to G-protein-coupled receptors [23], thus, ADHR antagonists were employed to explore the potential link between ADH and PKA/ PKC in psychological stress asthma. In view of the potential regulatory network between ADHR subtypes (V1A, V2) and PKA/PKC in vascular smooth muscle cell (VSMC) [35] and other cells [36, 37], SR-49059 (V1A antagonist) and SR-121463A (V2 antagonist) were selected.…”

“…Moreover, ADH has been proven to exert effects through binding to ADHR, primarily V1A and V2 receptors [16, 42]. Given that common ADHR subtypes (V1A, V1B, and V2) are members of the seven transmembrane domain G-protein-coupled receptor superfamily [34], and the significant participation of PKA and PKC in cell signaling pathways linked to G-protein-coupled receptors [23], the hypothesis was tested whether PKA and PKC were associated with ADH in psychological stress asthma, as studied using two different ADHR antagonists. We observed that ADHR antagonists signally suppressed higher protein levels of PKAα and PKCα after psychological stress stimulation as compared to OVA alone, indicating the correlation between ADH and PKA/PKC in psychological stress asthma.…”

“…Western blotting was performed as reported earlier [23]. Lung tissues detached from the mice were homogenized and centrifuged, then 20 µl of supernatant and gel loading solution were mixed.…”

“…Thus, in view of the link between neuroendocrine-immune axis and psychological stress in the development of asthma, the hypothesis was that ADH participated in the course of psychological stress asthma. Furthermore, considering that the well-known ADHR subtypes (V1A, V1B, and V2) are members of the seven transmembrane domain G-protein-coupled receptor family [22], and cAMP-protein kinase (PKA) and Ca + -dependent/independent protein kinase (PKC) are important signal transduction factors implicated in cell signaling pathways linked to G-protein-coupled receptors [23], hence, in this study, we not only examined ADH and ADHR levels, but also clarified the role of PKA/PKC signal pathway in a mouse model of psychological stress asthma.…”