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School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, UK

(Correspondence should be addressed to F Xiao who is now at The Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6AE, UK; Email: f.xiao{at}ucl.ac.uk)

The extracellular N-terminus of G-protein-coupled receptors may be involved in signalling events. We examined this in the angiotensin II type 1 receptor (AT1-R) using monoclonal antibody 6313/G2, raised against a conserved sequence in the N-terminal domain, and found it evokes inhibitory and stimulatory responses. In rat aortic smooth muscle cell (RASMC) primary cultures, 6313/G2 (2.5 µg/ml) inhibited both basal and angiotensin II (Ang II; 10^–7 mol/l)-stimulated [H³]thymidine incorporation. Exposure to 6313/G2 gave sustained increases in phosphorylated protein kinase C (PKC) but gave a decrease in phosphorylated p44/42 extracellular signal-regulated kinases (ERK1/2) sustained from 10 min to 48 h compared with untreated control RASMC. In contrast, Ang II had no effect on PKC, and, though it is acutely stimulatory (up to 5 min), it had no sustained effect on ERK1/2 either. Using Fura-2 and microfluorimetry, 6313/G2 added alone induced a transient increase in intracellular calcium ([Ca²⁺]_i), with a characteristic response curve different from that of Ang II itself. The antibody was without effect on an Ang II-stimulated activator protein-1 reporter system, though it reduced unstimulated reporter activity. Such discriminatory effects on intracellular signalling suggest that the AT1-R N-terminus itself might be a target for therapeutic intervention in chronic vascular disease.