The involvement of the P2 receptor in the activation of ERK induced by a short transient fluid flow stimulation in MC3T3-E1 osteoblasts was examined in the current study. The ERK activation induced by this transient fluid flow stimulation was followed by an increase in c-fos mRNA expression. Suramin, a nonselective P2 receptor antagonist, and two different P2X7 receptor (P2X7R) antagonists, ATP analogue (oxidized ATP) and dye (Brilliant blue G), inhibited fluid flow-induced ERK activation. However, the P2Y receptor pathway inhibitor U73122 did not abolish this ERK activation. The P2X7R agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP) significantly increased ERK activation and this activation could be completely inhibited by oxidized ATP and Brilliant blue G. Our results suggest that P2X7R is a highly sensitive P2 receptor for fluid flow-induced ERK activation in osteoblasts. (C) 2008 Elsevier Inc. All rights reserved.