Amyloid beta (A beta) Peptide Directly Activates Amylin-3 Receptor Subtype by Triggering Multiple Intracellular Signaling Pathways

作者：Fu Wen; Ruangkittisakul Araya; MacTavish David; Shi Jenny Y; Ballanyi Klaus; Jhamandas Jack H^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287(22): 18820-18830.

DOI：10.1074/jbc.M111.331181

The two age-prevalent diseases Alzheimer disease and type 2 diabetes mellitus share many common features including the deposition of amyloidogenic proteins, amyloid beta protein (A beta) and amylin (islet amyloid polypeptide), respectively. Recent evidence suggests that both A beta and amylin may express their effects through the amylin receptor, although the precise mechanisms for this interaction at a cellular level are unknown. Here, we studied this by generating HEK293 cells with stable expression of an isoform of the amylin receptor family, amylin receptor-3 (AMY3). A beta 1-42 and human amylin (hAmylin) increase cytosolic cAMP and Ca2+, trigger multiple pathways involving the signal transduction mediators protein kinase A, MAPK, Akt, and cFos. A beta 1-42 and hAmylin also induce cell death during exposure for 24-48 h at low micromolar concentrations. In the presence of hAmylin, A beta 1-42 effects on HEK293-AMY3-expressing cells are occluded, suggesting a shared mechanism of action between the two peptides. Amylin receptor antagonist AC253 blocks increases in intracellular Ca2+, activation of protein kinase A, MAPK, Akt, cFos, and cell death, which occur upon AMY3 activation with hAmylin, A beta 1-42, or their co-application. Our data suggest that AMY3 plays an important role by serving as a receptor target for actions A beta and thus may represent a novel therapeutic target for development of compounds to treat neurodegenerative conditions such as Alzheimer disease.

• 出版日期2012-5-25