PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex

CONTEXT: Primary pigmented nodular adrenocortical disease, associated with Carney complex, is caused by mutations in PRKAR1A (mt-PRKAR1A), a gene that codes for the regulatory subunit type 1alpha (RIalpha) of cAMP-dependent protein kinase (PKA). PRKAR1A inactivation is associated with dysregulated PKA activity that is thought to result in tumorigenesis. mt-PRKAR1A-bearing lymphocytes from Carney complex patients exhibit enhanced cell proliferation associated with increased expression of the MAPK ERK1/2 pathway. OBJECTIVE: The objective of the study was to determine how PKA and its subunits and ERK1/2 and their molecular partners change in the presence of PRKAR1A mutations in adrenocortical tissue. DESIGN: PKA activity and subunit expression, ERK1/2, other immunoassays, and immunohistochemistry on adrenocortical samples from patients with germline normal or mt-PRKAR1A were analyzed. RESULTS: Increased cAMP-stimulated total kinase activity was associated with mt-PRKAR1A. PKA subunit expression analysis in mt-PRKAR1A tissues, by quantitative mRNA assay and immunoblotting, showed a 2.4-fold (P = 0.02) and 1.8-fold (P = 0.09) decrease in RIalpha's message and protein, respectively, and increases in other PKA subunits. Immunoassays showed 2-fold (P = 0.03) and 6-fold (P = 0.03) decreases in baseline ERK1/2, with corresponding increases in phosphorylated (p) ERK1/2 in mt-PRKAR1A samples. B-raf kinase, p-MEK1/2, and p-c-Myc, but not p-Akt/protein kinase B, were significantly increased. Immunohistochemistry studies supported these data. CONCLUSIONS: mt-PRKAR1A causes increased total cAMP-stimulated kinase activity, likely the result of up-regulation of other PKA subunits caused by down-regulation of RIalpha, as seen in human lymphocytes and mouse animal models. These changes, associated with enhanced MAPK activity, may be, in part, responsible for the proliferative signals that result in primary pigmented nodular adrenocortical disease.     

St John's wort for depression: Time for a different perspective?

OBJECTIVES: To review the development of the evidence on the herbal remedy, St John's wort (SJW) (Hypericum perforatum), in the treatment of depression. METHODS: Searches of major biomedical and specialist databases including EMBASE, MEDLINE, PsycINFO, AMED and HerbMed were conducted. Searches aimed to identify quantitative research (systematic reviews and meta-analyses) and relevant qualitative studies. Data were extracted systematically. RESULTS: Systematic reviews have been published regularly over the past 10 years. Methodology has varied resulting in differing estimates of effectiveness but overall findings have been positive when compared with placebo for mild to moderate depression. Recent reviews have focused on adverse effects and interactions. One qualitative study focusing on SJW in depression was retrieved. CONCLUSIONS: SJW has received intensive and continued attention since initial indications of its potential effectiveness for depression. The focus appears to be moving from effectiveness to safety but the patient's perspective has received less attention and may prove a valuable avenue for future studies.