Stimulation of β 3 ‐adrenoceptors causes phosphorylation of p38 mitogen‐activated protein kinase via a stimulatory G protein‐dependent pathway in 3T3‐L1 adipocytes

This study deals with phosphorylation and activation of p38 mitogen‐activated protein kinase (MAPK) via β 3 ‐adrenoceptor (AR) and the signal transduction pathway in 3T3‐L1 adipocytes. β 3 ‐AR agonist BRL37344A (10 n M ) caused phosphorylation and activation of p38 MAPK in 3T3‐L1 adipocytes but not in fibroblasts. BRL37344A and also the other β 3 ‐AR agonists, CGP12177A and SR58611A, caused p38 MAPK phosphorylation in dose‐dependent manners. The p38 MAPK phosphorylations by BRL37344A (10 n M ), CGP12177A (100 n M ), and SR58611A (10 n M ) were not antagonized by β 1 ‐ and β 2 ‐ARs antagonist 1 ‐propranolol (100 n M ) but blocked by β 3 ‐AR antagonist SR59230A (10 μ M ), suggesting the phosphorylation was caused via β 3 ‐AR. The phosphorylations of p38 MAPK were completely abolished by treatment with cholera toxin (CTX) but not pertussis toxin (100 ng ml −1 , 24 h). Activation of Gs by CTX (100 ng ml −1 ) and adenylyl cyclase by forskolin mimicked p38 MAPK phosphorylation. p38 MAPK phosphorylation by BRL37344A was reduced to almost 50% by cyclic AMP‐dependent protein kinase (PKA) inhibitors such as H89 (10 μ M ) and PKI (10 μ M ). A src‐family tyrosine kinases inhibitor PP2 (1 μ M ) also halved the p38 MAPK phosphorylation. Combined use of H89 (10 μ M ) and PP2 (10 μ M ) did not bring about further inhibition. These results suggest that β 3 ‐AR caused phosphorylation of p38 MAPK via Gs protein and partly through a pathway involving PKA and src‐family kinase(s), although the contribution of the unidentified pathway remains to be clarified.British Journal of Pharmacology (2002) 135 , 951–960; doi: 10.1038/sj.bjp.0704537