In:
PLOS ONE, Public Library of Science (PLoS), Vol. 18, No. 4 ( 2023-4-6), p. e0268363-
Abstract:
Positive allosteric modulators for free fatty acid receptor 2 (FFAR2/GPR43), that affect receptor function through binding to two distinct allosteric binding sites, were used to determine the correlation between the responses induced in neutrophils by two distinct activation modes; FFAR2 was activated either by the orthosteric agonist propionate or by a receptor transactivation mechanism that activated FFAR2 from the cytosolic side of the neutrophil plasma membrane by signals generated by the neutrophil PAFR (receptor for platelet activating factor), P2Y 2 R (receptor for ATP), FPR1 (receptor for fMLF) and FPR2 (receptor for WKYMVM). We show that the transactivation signals that activate FFAR2 in the absence of any orthosteric agonist were generated downstream of the signaling G protein that couple to PAFR and P2Y 2 R. This transactivation of allosterically modulated FFAR2s, by signals generated by PAFR/P2Y 2 R, represents a novel mechanism by which a G protein coupled receptor can be activated. Weak correlations were obtained when the FFAR2 activity was induced by the transactivation signals generated by PAFRs and P2Y 2 Rs were compared with the FFAR2 activity induced by the orthosteric agonist propionate. Comparison of the responses for each allosteric modulator revealed that the ratio values, calculated from the peak values of the ATP and propionate responses, varied from 0.2 to 1. Depending on the allosteric modulator, the response induced by the two different mechanisms (orthosteric activation and receptor transactivation, respectively), was equal or the propionate response was more pronounced. Importantly, we conclude that FFAR2 activation from outside (orthosteric activation) and inside (receptor cross-talk/transactivation) can be selectively affected by an allosteric FFAR2 modulator.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0268363
DOI:
10.1371/journal.pone.0268363.g001
DOI:
10.1371/journal.pone.0268363.g002
DOI:
10.1371/journal.pone.0268363.g003
DOI:
10.1371/journal.pone.0268363.g004
DOI:
10.1371/journal.pone.0268363.g005
DOI:
10.1371/journal.pone.0268363.g006
DOI:
10.1371/journal.pone.0268363.g007
DOI:
10.1371/journal.pone.0268363.g008
DOI:
10.1371/journal.pone.0268363.t001
DOI:
10.1371/journal.pone.0268363.t002
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2267670-3
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