Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
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Query: UNIPROT:P01185 (
vasopressin
)
23,126
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) activate numerous cellular signals through the combined actions of G proteins, GPCR kinases, and arrestins. Although arrestins have traditionally been thought of as mediating GPCR desensitization, they have now been shown to play important roles in the internalization, trafficking, and signaling of many GPCRs. We demonstrate that in cells devoid of arrestins, the stimulation of numerous GPCRs including the
N-formyl peptide receptor
(FPR) initiates rapid cell rounding, annexin V positivity, and caspase activation followed by cell death. The apoptotic response is initiated by G protein signaling and involves activation of phosphoinositide 3-kinase, mitogen-activated protein kinases, and c-Src resulting in cytochrome c release from mitochondria and ultimately caspase 9 and caspase 3 activation. Reconstitution with either arrestin-2 or arrestin-3 is completely sufficient to prevent FPR-mediated apoptosis. Surprisingly, a non-desensitizing and non-internalizing mutant of the FPR is unable to initiate apoptosis, indicating that receptor phosphorylation and internalization, but not solely chronic activation due to a lack of desensitization, are critical determinants for the induction of apoptosis by the FPR. We further demonstrate that this response is not unique to the FPR with numerous additional GPCRs, including the V2
vasopressin
, angiotensin II (type 1A), and CXCR2 receptors, capable of initiating apoptosis upon stimulation, whereas GPCRs such as the beta(2)-adrenergic receptor and CXCR4 are not capable of initiating apoptotic signaling. These data demonstrate for the first time that arrestins play a critical and completely unexpected role in the suppression GPCR-mediated apoptosis, which we show is a common consequence of GPCR-mediated cellular activation in the absence of arrestins.
...
PMID:Arrestins block G protein-coupled receptor-mediated apoptosis. 1505 14
G proteins are activated when they associate with G protein-coupled receptors (GPCRs), often in response to agonist-mediated receptor activation. It is generally thought that agonist-induced receptor-G protein association necessarily promotes G protein activation and, conversely, that activated GPCRs do not interact with G proteins that they do not activate. Here we show that GPCRs can form agonist-dependent complexes with G proteins that they do not activate. Using cell-based bioluminescence resonance energy transfer (BRET) and luminescence assays we find that
vasopressin
V
2
receptors (V
2
R) associate with both G
s
and G
12
heterotrimers when stimulated with the agonist arginine vasopressin (AVP). However, unlike V
2
R-G
s
complexes, V
2
R-G
12
complexes are not destabilized by guanine nucleotides and do not promote G
12
activation. Activating V
2
R does not lead to signaling responses downstream of G
12
activation, but instead inhibits basal G
12
-mediated signaling, presumably by sequestering G
12
heterotrimers. Overexpressing G
12
inhibits G protein receptor kinase (GRK) and arrestin recruitment to V
2
R and receptor internalization. Formyl peptide (
FPR1
and FPR2) and Smoothened (Smo) receptors also form complexes with G
12
that are insensitive to nucleotides, suggesting that unproductive GPCR-G
12
complexes are not unique to V
2
R. These results indicate that agonist-dependent receptor-G protein association does not always lead to G protein activation and may in fact inhibit G protein activation.
...
PMID:Agonist-induced formation of unproductive receptor-G
12
complexes. 3281 60
