MRP4 and CFTR in the regulation of cAMP and β-adrenergic contraction in cardiac myocytes

Zachary M. Sellers, Anjaparavanda P. Naren, Yang Kevin Xiang, Philip M. Best

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Spatiotemporal regulation of cAMP in cardiac myocytes is integral to regulating the diverse functions downstream of β-adrenergic stimulation. The activities of cAMP phosphodiesterases modulate critical and well-studied cellular processes. Recently, in epithelial and smooth muscle cells, it was found that the multi-drug resistant protein 4 (MRP4) acts as a cAMP efflux pump to regulate intracellular cAMP levels and alter effector function, including activation of the cAMP-stimulated Cl - channel, CFTR (cystic fibrosis transmembrane conductance regulator). In the current study we investigated the potential role of MRP4 in regulating intracellular cAMP and β-adrenergic stimulated contraction rate in cardiac myocytes. Cultured neonatal ventricular myocytes were used for all experiments. In addition to wildtype mice, β 1-, β 2-, and β 12-adrenoceptor, and CFTR knockout mice were used. MRP4 expression was probed via Western blot, intracellular cAMP was measured by fluorescence resonance energy transfer, while the functional role of MRP4 was assayed via monitoring of isoproterenol-stimulated contraction rate. We found that MRP4 is expressed in mouse neonatal ventricular myocytes. A pharmacological inhibitor of MRP4, MK571, potentiated submaximal isoproterenol-stimulated cAMP accumulation and cardiomyocyte contraction rate via β 1-adrenoceptors. CFTR expression was critical for submaximal isoproterenol-stimulated contraction rate. Interestingly, MRP4-dependent changes in contraction rate were CFTR-dependent, however, PDE4-dependent potentiation of contraction rate was CFTR-independent. We have shown, for the first time, a role for MRP4 in the regulation of cAMP in cardiac myocytes and involvement of CFTR in β-adrenergic stimulated contraction. Together with phosphodiesterases, MRP4 must be considered when examining cAMP regulation in cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)80-87
Number of pages8
JournalEuropean Journal of Pharmacology
Volume681
Issue number1-3
DOIs
StatePublished - Apr 15 2012
Externally publishedYes

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Cardiac Myocytes
Adrenergic Agents
Pharmaceutical Preparations
Proteins
Isoproterenol
Phosphoric Diester Hydrolases
Adrenergic Receptors
Muscle Cells
Fluorescence Resonance Energy Transfer
Knockout Mice
Smooth Muscle Myocytes
Western Blotting
Pharmacology

Keywords

  • β-Adrenergic signaling
  • cAMP
  • Cardiac myocyte
  • CFTR
  • MRP4

ASJC Scopus subject areas

  • Pharmacology

Cite this

MRP4 and CFTR in the regulation of cAMP and β-adrenergic contraction in cardiac myocytes. / Sellers, Zachary M.; Naren, Anjaparavanda P.; Xiang, Yang Kevin; Best, Philip M.

In: European Journal of Pharmacology, Vol. 681, No. 1-3, 15.04.2012, p. 80-87.

Research output: Contribution to journalArticle

Sellers, Zachary M. ; Naren, Anjaparavanda P. ; Xiang, Yang Kevin ; Best, Philip M. / MRP4 and CFTR in the regulation of cAMP and β-adrenergic contraction in cardiac myocytes. In: European Journal of Pharmacology. 2012 ; Vol. 681, No. 1-3. pp. 80-87.
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