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J. Biol. Chem., Vol. 279, Issue 1, 356-362, January 2, 2004

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The Caveolin Scaffolding Domain Modifies 2-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate Receptor Binding Properties by Inhibiting Phospholipase A₂ Activity^*

Sophie B. Gaudreault, Chantale Chabot, Jean-Philippe Gratton, and Judes Poirier¶||

From the Douglas Hospital Research Center, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H4A 2B4, Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, and the ^¶McGill Centre for Studies in Aging, Verdun, Quebec H4H 1R3, Canada

Activation of the enzyme phospholipase (PLA ₂) has been proposed to be part of the molecular mechanism involved in the alteration of 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptor responsiveness during long term changes in synaptic plasticity (long term potentiation). This study assesses the effect of the caveolin-1 scaffolding domain (CSD) on the activity of the regulatory enzyme PLA₂. Caveolin-1 is a 22-kDa cholesterol-binding membrane protein known to inhibit the activity of most of its interacting partners. Our results show that the calcium-dependent cytosolic form of PLA₂ (cPLA₂) and caveolin-1 co-localized in mouse primary hippocampal neuron cultures and that they were co-immunoprecipitated from mouse hippocampal homogenates. A peptide corresponding to the scaffolding domain of caveolin-1 (Cav-(82-101)) dramatically inhibited cPLA₂ activity in purified hippocampal synaptoneurosomes. Activation of endogenous PLA₂ activity with KCl or melittin increased the binding of [³H]AMPA to its receptor. This effect was almost completely abolished by the addition of the CSD peptide to these preparations. Moreover, we demonstrated that the inhibitory action of the CSD peptide on AMPA receptor binding properties is specific (because a scrambled version of this peptide failed to have any effect) and that it is mediated by an inhibition of PLA₂ enzymatic activity (because the CSD peptide failed to have an effect in membrane preparations lacking endogenous PLA₂ activity). These results raised the possibility that caveolin-1, via the inhibition of cPLA₂ enzymatic activity, may interfere with synaptic facilitation and long term potentiation formation in the hippocampus.

Received for publication, May 7, 2003 , and in revised form, October 9, 2003.

^* This work was supported by the Canadian Institute for Health Research (to J. P.), the Natural Sciences and Engineering Research Council (to S. B. G.), Fonds de la Recherche en Santé du Québec (to C. C., and S. B. G.) and Alzheimer Society of Canada (to J. P., and S. B. G.). 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: Director, McGill Center for Studies in Aging, 6825 Blvd. LaSalle, Verdun, Quebec H4H 1R3, Canada. Tel.: 514-766-2010; Fax: 514-888-4094. E-mail: judes.poirier{at}mcgill.ca.

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