P2‐307: Glucocorticoids inhibit PKA/CREB pathway through modulation of protein level of RIIα subunit of PKA

Clinical evidences have suggested a link between glucocorticoids(GCs) and memory deficits. Protein kinase A(PKA), on activation, phophorylates cAMP-response element binding protein(CREB) and this PKA/CREB pathway plays a major role in memory formation. The impairment of PKA/CREB pathway contributes to the memory deficits in many neurodegenerative diseases including Alzheimer's disease(AD). However, how GCs affect this pathway remains elusive. We examined the relationship between GCs and PKA/CREB pathway in both HEK293 cells stably expressing tau441(HEK293/tau441 cells) and wild-type HEK293 cells. We found that administration of GCs decreased phosphorylated CREB(pCREB) levels while increased CREB and phosphorylation of tau at Ser214 in HEK293/tau441 cells. The downregulation of pCREB was partially caused by increased protein levels of RIIα subunit of PKA, since upregulation of RIIα subunit could decrease PKA activity. In contrast, wild-type HEK293 cells did not show above alterations of PKA subunits although a slightly decreased level of pCREB could still be observed. Collectively, these results indicated that protein level of RIIα subunit of PKA was involved in GCs-induced downregulation of PKA/CREB pathway activity and this alteration might depend on the overexpression of tau.