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(Circulation Research. 2004;95:e98.)
© 2004 American Heart Association, Inc.

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Peptidyl-Glycine -Amidating Monooxygenase Targeting and Shaping of Atrial Secretory Vesicles

Inhibition by Mutated N-Terminal ProANP and PBA

Vénus Labrador, Cécile Brun, Stéphane König, Angela Roatti, Alex J. Baertschi

From the Department of Neuroscience, Centre Médical Universitaire, University of Geneva, Switzerland.

Correspondence Dr Alex J. Baertschi, Neuroscience, CMU, 1 Rue Michel-Servet, 1211 Geneva 4, Switzerland. E-mail alex.baertschi{at}medecine.unige.ch

ANP (atrial natriuretic peptide) is widely recognized as an important vasorelaxant, diuretic, and cardioprotective hormone. Little is known, however, about how ANP-secretory vesicles form within the atrial myocytes. Secretory vesicles were visualized by fluorescence microscope imaging in live rat atrial myocytes expressing proANP–enhanced green fluorescent protein (EGFP), or N-terminal–mutated fusion proteins thought to suppress the calcium-dependent aggregation of proANP. Results showed the following: (1) aggregates of proANP and coexpressed proANP-EGFP recruited peptidylglycine -amidating monooxygenase (PAM)-1, an abundant atrial integral vesicle membrane protein; (2) coexpressed N-terminal–mutated (Glu23,24Gln23,24) and N-terminal–deleted proANP-EGFP inhibited recruitment of PAM-1 by up to 60%; (3) 4-phenyl-3-butenoic acid (PBA) (10 µmol/L), a pharmacological inhibitor of the lumenal peptidylglycine -hydroxylating monooxygenase domain of PAM proteins, inhibited recruitment of endogenous PAM-1 and of coexpressed pro-EGFP–PAM-1; (4) PBA had no effect on exocytosis of the potassium inward rectifier KIR2.1; (5) PBA induced a deformation of the secretory vesicles but did not inhibit docking. These findings suggest that recruitment of PAM-1 to secretory vesicles depends on intact N-terminal proANP and on the lumenal domain of PAM-1. Conversely, PAM-1 participates in shaping the proANP-secretory vesicles. The full text of this article is available online at http://circres.ahajournals.org.

Key Words: atrium • EGFP • in vivo imaging • PAM • proANP • secretory vesicles

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