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First published on April 18, 2005; DOI: 10.1124/mol.105.011692

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Qing Yang
Regina Alemany
Klara Kitajka
Stephen M. Lanier
Pablo V. Escriba
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Received for publication February 9, 2005.
Revised April 15, 2005.
Accepted for publication April 15, 2005.

Influence of the membrane lipid structure on signal processing via G protein-coupled receptors

Qing Yang 1, Regina Alemany 2, Jesus Casas 2, Klara Kitajka 2, Stephen M. Lanier 3, Pablo V. Escriba 2*

1 Medical University of South Carolina 2 University of the Balearic Islands 3 Louisiana State University Health Sciences Center

* Address correspondence to: E-mail: pablo.escriba{at}uib.es

Abstract

We have recently reported that the lipid structure regulates the interaction with membranes, recruitment to membranes and distribution to membrane domains of heterotrimeric G{alpha}{beta}{gamma} proteins, G{alpha} subunits and G{beta}{gamma} dimers (J Biol Chem 279:36540-36545, 2004). Here, we demonstrate that modulation of the membrane structure not only determines G protein localization, but also regulates the function of G proteins and related signaling proteins. In this context, the antitumor drug daunorubicin (daunomycin) and oleic acid changed the membrane structure and inhibited G protein activity in biological membranes. They also induced marked changes in the activity of the {alpha}2A/D-adrenergic receptor and adenylyl cyclase. In contrast, elaidic and stearic acid, did not change the activity of the above proteins. These fatty acids are chemical but not structural analogs of oleic acid, supporting the structural basis of the modulation of membrane lipid organization and subsequent regulation of G protein-coupled receptor signaling. In addition, oleic acid (and also daunorubicin) did not alter G protein activity in a membrane-free system, further demonstrating the involvement of the membrane structure in this signal modulation. The present work also unravels in part the molecular bases involved in the antihypertensive (Hypertension 43:249-254, 2004) and anticancer (Mol Pharmacol 67:531-540, 2005) activities of synthetic oleic acid derivatives (e.g. 2-hydroxyoleic acid), as well as the molecular bases of the effects of diet fats on human health.


Key words: G protein regulation, Lipid rafts/microdomains, Membrane targets


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