INVOLVEMENT OF P62 NUCLEOPORIN IN ANGIOTENSIN-II-INDUCED NUCLEAR TRANSLOCATION OF STAT3 IN BRAIN NEURONS

Chronic stimulation of brain neurons by angiotensin II (Ang II) result s in a increase in norepinephrine (NE) uptake. This involves stimulati on of transcription of NE transporter and tyrosine hydroxylase genes a nd is associated with translocation of signaling molecules and transcr iption factors from the cytoplasmic compartment into the neuronal nucl eus (Lu et al., 1996a), We report here that the phosphorylation of p62 , a glycoprotein nucleoporin of the nuclear pore complex (NPC), by MAP kinase is involved in this process. Ang II caused a time-dependent tr anslocation of signal transducers and activators of transcription (STA T3) from the cytoplasmic compartment into the nucleus, This translocat ion was attenuated by pretreatment with antisense oligonucleotide (AON ) to MAP kinase. Ang II also stimulated phosphorylation of p62, and a maximal phosphorylation of 12-fold was observed with 100 nM Ang II. Th is stimulation was blocked by losartan, an AT(1) receptor subtype-spec ific antagonist, The conclusion that MAP kinase is involved in Ang Ii- induced phosphorylation of p62 and nuclear translocation of STAT3 is s upported by the following. (1) p62 phosphorylation was blocked by a pe ptide that competes with p62 as a MAP kinase substrate both in vitro a nd in vivo; (2) AON to MAP kinase attenuated Ang II stimulation of p62 phosphorylation; al-td (3) in addition, it also blocked nuclear trans location of STAT3. Intracellular loading of the peptide containing MAP kinase substrate consensus of the p62 reduced Ang II stimulation of p 62 phosphorylation and nuclear translocation of STAT3 in both in vivo and in vitro experiments, These observations suggest that Ang Ii-induc ed phosphorylation of p62 may accelerate the activity of the NPC, whic h would result in an increase in the nuclear transport of transcriptio n factors and signaling molecules. This will stimulate transcriptional processes associated with Ang II regulation of NE neuromodulation.