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J. Biol. Chem., Vol. 281, Issue 29, 20252-20262, July 21, 2006

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A Novel Role for Protein Phosphatase 2A in Receptor-mediated Regulation of the Cardiac Sarcolemmal Na⁺/H⁺ Exchanger NHE1^*

From the Cardiovascular Division, King's College London, London SE1 7EH, United Kingdom

G_q protein-coupled receptor stimulation increases sarcolemmal Na⁺/H⁺ exchanger (NHE1) activity in cardiac myocytes by an ERK/RSK-dependent mechanism, most likely via RSK-mediated phosphorylation of the NHE1 regulatory domain. Adenosine A₁ receptor stimulation inhibits this response through a G_i protein-mediated pathway, but the distal inhibitory signaling mechanisms are unknown. In cultured adult rat ventricular myocytes (ARVM), the A₁ receptor agonist cyclopentyladenosine (CPA) inhibited the increase in NHE1 phosphorylation induced by the ₁-adrenoreceptor agonist phenylephrine, without affecting activation of the ERK/RSK pathway. CPA also induced significant accumulation of the catalytic subunit of type 2A protein phosphatase (PP2A_c) in the particulate fraction, which contained the cellular NHE1 complement; this effect was abolished by pretreatment with pertussis toxin to inactivate G_i proteins. Confocal immunofluorescence microscopic imaging of CPA-treated ARVM revealed significant co-localization of PP2A_c and NHE1, in intercalated disc regions. In an in vitro assay, purified PP2A_c dephosphorylated a GST-NHE1 fusion protein containing aa 625-747 of the NHE1 regulatory domain, which had been pre-phosphorylated by recombinant RSK; such dephosphorylation was inhibited by the PP2A-selective phosphatase inhibitor endothall. In intact ARVM, the ability of CPA to attenuate the phenylephrine-induced increase in NHE1 phosphorylation and activity was lost in the presence of endothall. These studies reveal a novel role for the PP2A holoenzyme in adenosine A₁ receptor-mediated regulation of NHE1 activity in ARVM, the mechanism of which appears to involve G_i protein-mediated translocation of PP2A_c and NHE1 dephosphorylation.

Received for publication, January 10, 2006 , and in revised form, May 11, 2006.

^* This work was supported by the Medical Research Council, through Cooperative Group Core and Component Grants (G0001112 and G0001226), and by the British Heart Foundation, through an Intermediate Research Fellowship (FS/04/053). 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.

¹ To whom correspondence should be addressed: Cardiovascular Division, King's College London, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK. Tel.: 44-20-7188-3899; Fax: 44-20-7928-0658; E-mail: metin. avkiran{at}kcl.ac.uk.

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