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J. Biol. Chem., Vol. 279, Issue 19, 19421-19430, May 7, 2004

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Mechanism of Collagen Activation in Human Platelets^*

Diane E. Roberts, Archibald McNicol¶, and Ratna Bose||

From the Departments of Pharmacology and Therapeutics and ^¶Oral Biology, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada

The mechanism of collagen-induced human platelet activation was examined using Ca²⁺, Na⁺, and the pH-sensitive fluorescent dyes calcium green/fura red, sodium-binding benzofuran isophthalate, and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Administration of a moderate dose of collagen (10 µg/ml) to human platelets resulted in an increase in [Ca²⁺]_i and platelet aggregation. The majority of this increase in [Ca²⁺]_i resulted from the influx of calcium from the extracellular milieu via the Na⁺/Ca²⁺ exchanger (NCX) functioning in the reverse mode and was reduced in a dose-dependent manner by the NCX inhibitors 5-(4-chlorobenzyl)-2',4'-dimethylbenzamil (KD₅₀ = 4.7 ± 1.1 µM) and KB-R7943 (KD₅₀ = 35.1 ± 4.8 µM). Collagen-induced platelet aggregation was dependent on an increase in [Ca²⁺]_i and could be inhibited by chelation of intra- and extracellular calcium through the administration of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM) and EGTA, respectively, or via the administration of BAPTA-AM to platelets suspended in no-Na⁺/HEPES buffer. Collagen induced an increase in [Na⁺]_i (23.2 ± 7.6 mM) via the actions of thromboxane A₂ and, to a lesser extent, of the Na⁺/H⁺ exchanger. This study demonstrates that the collagen-induced increase in [Ca²⁺]_i is dependent on the concentration of Na⁺ in the extracellular milieu, indicating that the collagen-induced increase in [Na⁺]_i causes the reversal of the NCX, ultimately resulting in an increase in [Ca²⁺]_i and platelet aggregation.

Received for publication, August 11, 2003 , and in revised form, February 9, 2004.

^* This work was supported in part by the Heart and Stroke Foundation of Manitoba, Canada (to R. B.). 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.

Recipient of a Health Sciences Centre Foundation studentship.

^|| To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, University of Manitoba, A311, 753 McDermot Ave., Winnipeg, Manitoba R3E 0W3, Canada. Tel.: 204-789-3562; Fax: 204-789-3932; E-mail: rbose{at}ms.umanitoba.ca.

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