P2Y2 receptor signaling in neutrophils is regulated from inside by a novel cytoskeleton-dependent mechanism. Academic Article uri icon

start page

  • 242

end page

  • 252

abstract

  • Functional selectivity, a process by which G-protein coupled receptors (GPCRs) can activate one signaling route while avoiding another, is regulated by ligand-mediated stabilization of specific receptor states that modulate different downstream signaling events. We propose a novel mechanism for functional selectivity, induced by the endogenous P2Y2R agonist ATP and regulated at the signaling interface by the cytoskeleton. Upon ATP stimulation of human neutrophils, a transient rise in the cytosolic concentration of free Ca(2+) was not followed by activation of the superoxide anion-generating NADPH-oxidase. This was in contrast to signals generated through the formyl peptide receptor 1 (FPR1), as its activation was accompanied by both a mobilization of Ca(2+) and activation of the NADPH-oxidase. The phospholipase C/Ca(2+) signaling route is not modulated by the cytoskeleton-disrupting drug latrunculin A, but this drug was able to launch a new signaling route downstream of P2Y2R that led to NADPH-oxidase activation. The signaling downstream of P2Y2R was rapidly terminated and the receptors were desensitized; however, in contrast to desensitized FPR1, no P2Y2 receptor reactivation could be induced by latrunculin A. Thus, P2Y2R desensitization does not appear to involve the cytoskeleton, contrary to FPR1 desensitization. In summary, we hereby describe how ATP regulates functional selectivity via the cytoskeleton, leading to intracellular Ca(2+) increase, alone or with simultaneous NADPH-oxidase activation in neutrophils.Copyright © 2015 Elsevier Inc. All rights reserved.

date/time value

  • August 2015

Digital Object Identifier (DOI)

  • 10.1016/j.yexcr.2015.07.014

PubMed Identifier

  • 26192818

volume

  • 336

number

  • 2

keywords

  • Adenosine Triphosphate
  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Calcium
  • Cells, Cultured
  • Cytoskeleton
  • Depsipeptides
  • Enzyme Activation
  • Humans
  • Membrane Potentials
  • NADPH Oxidase
  • Neutrophil Activation
  • Neutrophils
  • Pertussis Toxin
  • Receptors, Formyl Peptide
  • Receptors, Purinergic P2Y2
  • Signal Transduction
  • Thiazolidines
  • Type C Phospholipases