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P2Y2 receptor signaling in neutrophils Is regulated from inside by a novel cytoskeleton-dependent mechanism.

Journal article
Authors Michael Gabl
Malene Winther
Amanda Welin
Anna Karlsson
Tudor I Oprea
Johan Bylund
Claes Dahlgren
Huamei Forsman
Published in Experimental cell research
Volume 336
Issue 2
Pages 242-52
ISSN 1090-2422
Publication year 2015
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Institute of Odontology, Section 3
Pages 242-52
Language en
Links dx.doi.org/10.1016/j.yexcr.2015.07....
Subject categories Basic Medicine

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.

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