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Intracellular NAADP increase induced by extracellular NAADP via the P2Y11-like receptor

Zoubir Djerada1, Hervé Millart

  • 1Department of Pharmacology, E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims Cedex, France. zoubir.djerada@univ-reims.fr

Biochemical and Biophysical Research Communications
|June 4, 2013
PubMed

Insights

Extracellular nicotinic acid adenine dinucleotide phosphate (NAADP) stimulates intracellular NAADP increase via the P2Y11-like receptor. This pathway involves Gs/ADP-ribosyl cyclase activity and impacts cardiovascular function.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Pharmacology
  • Cell Signaling

Background:

  • P2Y11-like and β-adrenergic receptors are crucial for cardiovascular regulation.
  • Both receptor types are implicated in myocardial preconditioning.
  • Extracellular NAADP's role in intracellular signaling requires elucidation.

Purpose of the Study:

  • To identify a signaling pathway for extracellular NAADP-induced intracellular NAADP increase.
  • To determine the involvement of the P2Y11-like receptor in this pathway.
  • To investigate the functional consequences in the cardiovascular system.

Main Methods:

  • Langendorff perfusion model for inotropic response assessment.
  • Cardiomyocyte cultures for direct intracellular measurements.
  • Selective P2Y11 receptor agonist (NF546) and antagonist (NF157) for pathway validation.

Main Results:

  • Extracellular NAADP induced a positive inotropic response via P2Y11-like receptor stimulation.
  • P2Y11-like receptor activation increased intracellular cyclic ADP-ribose (cADPr) and NAADP.
  • NF546 confirmed P2Y11-like receptor involvement, while NF157 blocked the observed increases.
  • Response profile mimicked β-adrenergic stimulation, indicating Gs/ADP-ribosyl cyclase activity.

Conclusions:

  • A novel signaling pathway is identified: extracellular NAADP increases intracellular NAADP via P2Y11-like receptor metabotropic activity.
  • This pathway likely contributes to intracellular calcium increases induced by extracellular NAADP.
  • The P2Y11-like receptor plays a significant role in regulating intracellular NAADP levels and cardiovascular function.

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