The Hippocampal Cholinergic Neurostimulating Peptide, the N-terminal Fragment of the Secreted Phosphatidylethanolamine-binding Protein, Possesses a New Biological Activity on Cardiac Physiology^*

Yannick Goumon, Tommaso Angelone, Françoise Schoentgen¶, Sylvette Chasserot-Golaz||, Bjorg Almas**, Miriam M. Fukami**, Keith Langley, Ingeborg D. Welters, Bruno Tota, Dominique Aunis, , and Marie-Hélène Metz-Boutigue

INSERM Unité 575, Physiopathologie du Système Nerveux, IFR 37, 67084 Strasbourg, France, Laboratory of Cardiovascular Physiology, Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende, Italy, ^¶CNRS UPR 4301, Centre de Biophysique Moléculaire, 45071 Orléans, France, ^||CNRS UPR 2356, Neurotransmission et Sécrétion Neuroendocrine, IFR 37, 67084 Strasbourg, France, ^**Department of Biochemistry and Molecular Biology, 5009 Bergen, Norway, and Department of Anaesthesiology, Intensive Care and Pain Medicine, Justus-Liebig-Universität, 35385 Giessen, Germany

Abstract: Phosphatidylethanolamine-binding protein (PEBP), alternatively named Raf-1 kinase inhibitor protein, is the precursor of the hippocampal cholinergic neurostimulating peptide (HCNP) corresponding to its natural N-terminal fragment, previously described to be released by hippocampal neurons. PEBP is a soluble cytoplasmic protein, also associated with plasma and reticulum membranes of numerous cell types. In the present report, using biochemistry and cell biology techniques, we report for the first time the presence of PEBP in bovine chromaffin cell, a well described secretion model. We have examined its presence at the subcellular level and characterized this protein on both secretory granule membranes and intragranular matrix. In addition, its presence in bovine chromaffin cell and platelet exocytotic medium, as well as in serum, was reported showing that it is secreted. Like many other proteins that lack signal sequence, PEBP may be secreted through non-classic signal secretory mechanisms, which could be due to interactions with granule membrane lipids and lipid rafts. By two-dimensional liquid chromatography-tandem mass spectrometry, HCNP was detected among the intragranular matrix components. The observation that PEBP and HCNP were secreted with catecholamines into the circulation prompted us to investigate endocrine effects of this peptide on cardiovascular system. By using as bioassay an isolated and perfused frog (Rana esculenta) heart preparation, we show here that HCNP acts on the cardiac mechanical performance exerting a negative inotropism and counteracting the adrenergic stimulation of isoproterenol. All together, these data suggest that PEBP and HCNP might be considered as new endocrine factors involved in cardiac physiology.

Received for publication August 4, 2003. Revision received December 11, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 33-3-88-45-66-09; Fax: 33-3-88-60-08-06; E-mail: metz{at}neurochem.u-strasbg.fr.

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