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J. Biol. Chem., Vol. 282, Issue 47, 34542-34554, November 23, 2007

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Atrial Natriuretic Peptide Attenuates Elevations in Ca²⁺ and Protects Hepatocytes by Stimulating Net Plasma Membrane Ca²⁺ Efflux^*

Anne K. Green¹, Rebecca C. Stratton², Paul E. Squires, and Alec W. M. Simpson

From the Department of Biological Sciences, The University of Warwick, Gibbet Hill Road, Coventry CV4 7AL and the Department of Human Anatomy and Cell Biology, The University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom

Elevations in intracellular Ca²⁺ concentration and calpain activity are common early events in cellular injury, including that of hepatocytes. Atrial natriuretic peptide is a circulating hormone that has been shown to be hepatoprotective. The aim of this study was to examine the effects of atrial natriuretic peptide on potentially harmful elevations in cytosolic free Ca²⁺ and calpain activity induced by extracellular ATP in rat hepatocytes. We show that atrial natriuretic peptide, through protein kinase G, attenuated both the amplitude and duration of ATP-induced cytosolic Ca²⁺ rises in single hepatocytes. Atrial natriuretic peptide also prevented stimulation of calpain activity by ATP, taurolithocholate, or Ca²⁺ mobilization by thapsigargin and ionomycin. We therefore investigated the cellular Ca²⁺ handling mechanisms through which ANP attenuates this sustained elevation in cytosolic Ca²⁺. We show that atrial natriuretic peptide does not modulate the release from or re-uptake of Ca²⁺ into intracellular stores but, through protein kinase G, both stimulates plasma membrane Ca²⁺ efflux from and inhibits ATP-stimulated Ca²⁺ influx into hepatocytes. These findings suggest that stimulation of net plasma membrane Ca²⁺ efflux (to which both Ca²⁺ efflux stimulation and Ca²⁺ influx inhibition contribute) is the key process through which atrial natriuretic peptide attenuates elevations in cytosolic Ca²⁺ and calpain activity. Moreover we propose that plasma membrane Ca²⁺ efflux is a valuable, previously undiscovered, mechanism through which atrial natriuretic peptide protects rat hepatocytes, and perhaps other cell types, against Ca²⁺-dependent injury.

Received for publication, August 24, 2007

^* This work was supported in part by Wellcome Trust Grant 065845/Z/01. 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.

² Biotechnology and Biological Sciences Research Council funded Ph.D. student.

¹ To whom correspondence should be addressed. Tel.: 44-2476-574184; Fax: 44-2476-523701; E-mail: A.K.Green{at}warwick.ac.uk.

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