Presenilin regulates extracellular regulated kinase (Erk) activity by a protein kinase C alpha dependent mechanism

Presenilin (PS1 and PS2) mutations cause early-onset familial Alzheimer's disease (AD). In addition to affecting β-amyloid precursor protein (APP) processing and Aβ generation, PSs regulate a number of signaling pathways. We previously showed that PSs regulate both phospholipase C (PLC) and protein kinase C (PKC) α and γ activities. We also reported that PS double knockout mouse embryonic fibroblasts (MEFs) have reduced levels of PKCα and enhanced levels of PKCδ. Here, we determined whether the PS modulation of PLC/PKC has consequences for extracellular regulated kinase (Erk) signaling. Erk has been suggested to be important in AD pathology by modulating APP processing and tau phosphorylation. We found that knocking out PS1 or PS2 alone resulted in increased Erk activity and that this effect could be reversed by the PKCα inhibitor Gö6976. We also found that Erk activity following either PLC or PKC stimulation was significantly lower in PS double knockout cells and that treatment with the PKC activator phorbol 12,13-dibutyrate (PdBu) down-regulated total-Erk levels in all cells except PS double knockouts. These results demonstrate that PSs regulate Erk activity through a PKCα dependent pathway and that disruption of PLC/PKC signaling in the absence of both PS1 and PS2 results in lower downstream activation of Erk.     

Depression,sleeping pattern,and suicidal ideation among medical students in Bangladesh: a cross-sectional pilot study

Journal of Public Health - Depression is a major morbidity and the most common mental disorder among the medical students in medical schools globally. Undergraduate students suffer stress more due...     

Presenilin-mediated signal transduction

Presenilin proteins, mutated forms of which cause early onset familial Alzheimer's disease, are capable of modulating various cell signal transduction pathways, the most extensively studied of which has been intracellular calcium signalling. Disease causing presenilin mutations can potentiate inositol(1,4,5)trisphosphate (InsP3) mediated endoplasmic reticulum release due to calcium overload in this organelle, as well as attenuate capacitative calcium entry. Our own studies have shown a novel function for presenilins that involves regulation of acetylcholine muscarinic receptor-stimulated phospholipase C upstream of InsP3 regulated calcium release. This article reviews the mechanisms by which presenilins modulate intracellular calcium signalling and the role that deregulated calcium homeostasis could play in the pathogenesis of Alzheimer's disease.     

β(2)-Adrenoceptors increase translocation of GLUT4 via GPCR kinase sites in the receptor C-terminal tail

BACKGROUND AND PURPOSE

β-Adrenoceptor stimulation induces glucose uptake in several insulin-sensitive tissues by poorly understood mechanisms.

EXPERIMENTAL APPROACH

We used a model system in CHO-K1 cells expressing the human β₂-adrenoceptor and glucose transporter 4 (GLUT4) to investigate the signalling mechanisms involved.

KEY RESULTS

In CHO-K1 cells, there was no response to β-adrenoceptor agonists. The introduction of β₂-adrenoceptors and GLUT4 into these cells caused increased glucose uptake in response to β-adrenoceptor agonists. GLUT4 translocation occurred in response to insulin and β₂-adrenoceptor stimulation, although the key insulin signalling intermediate PKB was not phosphorylated in response to β₂-adrenoceptor stimulation. Truncation of the C-terminus of the β₂-adrenoceptor at position 349 to remove known phosphorylation sites for GPCR kinases (GRKs) or at position 344 to remove an additional PKA site together with the GRK phosphorylation sites did not significantly affect cAMP accumulation but decreased β₂-adrenoceptor-stimulated glucose uptake. Furthermore, inhibition of GRK by transfection of the βARKct construct inhibited β₂-adrenoceptor-mediated glucose uptake and GLUT4 translocation, and overexpression of a kinase-dead GRK2 mutant (GRK2 K220R) also inhibited GLUT4 translocation. Introducing β₂-adrenoceptors lacking phosphorylation sites for GRK or PKA demonstrated that the GRK sites, but not the PKA sites, were necessary for GLUT4 translocation.

CONCLUSIONS AND IMPLICATIONS

Glucose uptake in response to activation of β₂-adrenoceptors involves translocation of GLUT4 in this model system. The mechanism is dependent on the C-terminus of the β₂-adrenoceptor, requires GRK phosphorylation sites, and involves a signalling pathway distinct from that stimulated by insulin.