HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 19, 18696-18702, May 13, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/19/18696    most recent M500219200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Camden, J. M. Articles by Weisman, G. A. Search for Related Content PubMed PubMed Citation Articles by Camden, J. M. Articles by Weisman, G. A. Social Bookmarking                      What's this?

P2Y₂ Nucleotide Receptors Enhance -Secretase-dependent Amyloid Precursor Protein Processing^*

Jean M. Camden, Ann M. Schrader, Ryan E. Camden, Fernando A. González, Laurie Erb, Cheikh I. Seye, and Gary A. Weisman¶

From the Department of Biochemistry, University of Missouri-Columbia, Columbia, Missouri 65211 and the Department of Chemistry, University of Puerto Rico, Río Piedras, Puerto Rico 00931

The amyloid precursor protein (APP) is proteolytically processed by - and -secretases to release amyloid , the main component in senile plaques found in the brains of patients with Alzheimer disease. Alternatively, APP can be cleaved within the amyloid domain by -secretase releasing the non-amyloidogenic product sAPP, which has been shown to have neuroprotective properties. Several G protein-coupled receptors are known to activate -secretase-dependent processing of APP; however, the role of G protein-coupled nucleotide receptors in APP processing has not been investigated. Here it is demonstrated that activation of the G protein-coupled P2Y₂ receptor (P2Y₂R) subtype expressed in human 1321N1 astrocytoma cells enhanced the release of sAPP in a time- and dose-dependent manner. P2Y₂ R-mediated sAPP release was dependent on extracellular calcium but was not affected by 1,2-bis(2-aminophenoxy)ethane-N,N,N,-trimethylammonium salt, an intracellular calcium chelator, indicating that P2Y₂ R-stimulated intracellular calcium mobilization was not involved. Inhibition of protein kinase C (PKC) with GF109203 or by PKC down-regulation with phorbol ester pre-treatment had no effect on UTP-stimulated sAPP release, indicating a PKC-independent mechanism. U0126, an inhibitor of the mitogen-activated protein kinase pathway, partially inhibited sAPP release by UTP, whereas inhibitors of Src-dependent epidermal growth factor receptor transactivation by P2Y₂ Rs had no effect. The metalloprotease inhibitors phenanthroline and TAPI-2 and the furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone also diminished UTP-induced sAPP release. Furthermore, small interfering RNA silencing of an endogenous adamalysin, ADAM10 or ADAM17/TACE, partially suppressed P2Y₂R-activated sAPP release, whereas treatment of cells with both ADAM10 and ADAM17/TACE small interfering RNAs completely abolished UTP-activated sAPP release. These results may contribute to an understanding of the non-amyloidogenic processing of APP.

Received for publication, January 6, 2005 , and in revised form, March 8, 2005.

^* This study was supported by National Institutes of Health Grants 1 P01-AG18357 and 1 P20-RR15565 and the University of Missouri-Columbia Food for the 21st Century Program. 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: Dept. of Biochemistry, 540E Life Sciences Center, 1201 Rollins Rd., University of Missouri-Columbia, Columbia, MO 65211-7310. Tel.: 573-882-5005; Fax: 573-884-2537; E-mail: weismang{at}missouri.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S.-K. Cha, T. Wu, and C.-L. Huang Protein kinase C inhibits caveolae-mediated endocytosis of TRPV5 Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1212 - F1221. [Abstract] [Full Text] [PDF]

				G. Burnstock Physiology and Pathophysiology of Purinergic Neurotransmission Physiol Rev, April 1, 2007; 87(2): 659 - 797. [Abstract] [Full Text] [PDF]

				M. P. Abbracchio, G. Burnstock, J.-M. Boeynaems, E. A. Barnard, J. L. Boyer, C. Kennedy, G. E. Knight, M. Fumagalli, C. Gachet, K. A. Jacobson, et al. International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy Pharmacol. Rev., September 1, 2006; 58(3): 281 - 341. [Abstract] [Full Text] [PDF]

				H. Ohtsu, P. J. Dempsey, and S. Eguchi ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors Am J Physiol Cell Physiol, July 1, 2006; 291(1): C1 - C10. [Abstract] [Full Text] [PDF]