GPCR interacting proteins (GIP)

Bockaert, Joël; Fagni, Laurent; Dumuis, Aline; Marin, Philippe

doi:10.1016/j.pharmthera.2004.06.004

Cited by 245 publications

(175 citation statements)

References 144 publications

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“…This interaction adds to already known direct couplings of GPCRs with various effectors (45; for review, see ref. 46). We show, however, that the coupling of the GPCR to the release proteins is both voltage-and agonist-dependent.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release

Kupchik

Rashkovan

Ohana

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Ca 2؉ is essential for physiological depolarization-evoked synchronous neurotransmitter release. But, whether Ca 2؉ influx or another factor controls release initiation is still under debate. The time course of ACh release is controlled by a presynaptic inhibitory G protein-coupled autoreceptor (GPCR), whose agonist-binding affinity is voltage-sensitive. However, the relevance of this property for release control is not known. To resolve this question, we used pertussis toxin (PTX), which uncouples GPCR from its Gi/o and in turn reduces the affinity of GPCR toward its agonist. We show that PTX enhances ACh and glutamate release (in mice and crayfish, respectively) and, most importantly, alters the time course of release without affecting Ca 2؉ currents. These effects are not mediated by G␤␥ because its microinjection into the presynaptic terminal did not alter the time course of release. Also, PTX reduces the association of the GPCR with the exocytotic machinery, and this association is restored by the addition of agonist. We offer the following mechanism for control of initiation and termination of physiological depolarization-evoked transmitter release. At rest, release is under tonic block achieved by the transmitter-bound high-affinity presynaptic GPCR interacting with the exocytotic machinery. Upon depolarization, the GPCR uncouples from its G protein and consequently shifts to a low-affinity state toward the transmitter. The transmitter dissociates, the unbound GPCR detaches from the exocytotic machinery, and the tonic block is alleviated. The free machinery, together with Ca 2؉ that had already entered, initiates release. Release terminates when the reverse occurs upon repolarization.G protein-coupled receptor ͉ neurotransmitter release ͉ pertussis toxin ͉ presynaptic receptors C a 2ϩ influx is essential for physiological depolarizationinduced neurotransmitter (NT) release (1, 2). A broader, Ca 2ϩ voltage, hypothesis suggests that two factors control release: Ca 2ϩ and G protein-coupled receptors (GPCRs), whose agonist-binding affinity is voltage-dependent (3). The mechanism suggested for this control is as follows. (i) At resting potential and rest concentration (nMs) of transmitter, the release machinery (SNARE proteins and synaptotagmin) is under tonic block imposed by the transmitter-bound high-affinity (nMs) GPCR. (ii) Depolarization shifts the GPCR to a lowaffinity state ( Ms), resulting in rapid transmitter dissociation (it should be emphasized that at this stage release of NT did not occur yet, and the concentration of NT in the synapse is still in the nM range). (iii) The unbound GPCR detaches from the release machinery to relieve the tonic block. The free-release machinery together with Ca 2ϩ , which had already entered, initiates release. (iv) Upon repolarization, release terminates because the receptor returns to its high-affinity state and the tonic block is reinstated.Much of this suggested mechanism was supported experimentally (3-8) by using mainly the cholinergic neuromuscular junction (N...

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release

Kupchik

Rashkovan

Ohana

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, a number of other GPCRs have previously been shown to interact with PDZ domain-containing scaffolding proteins (see ref. 19 for review). Agonist potencies (EC50) and efficacies (Emax) were determined for agonist-mediated activation of PI hydrolysis, as described in Materials and Methods.…”

Section: Discussionmentioning

confidence: 99%

p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling

Sheffler¹,

Kroeze²,

Garcia

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) are essential for normal central CNS function and represent the proximal site(s) of action for most neurotransmitters and many therapeutic drugs, including typical and atypical antipsychotic drugs. Similarly, protein kinases mediate many of the downstream actions for both ionotropic and metabotropic receptors. We report here that genetic deletion of p90 ribosomal S6 kinase 2 (RSK2) potentiates GPCR signaling. Initial studies of 5-hydroxytryptamine (5-HT) 2A receptor signaling in fibroblasts obtained from RSK2 wild-type (؉͞؉) and knockout (؊͞؊) mice showed that 5-HT 2A receptor-mediated phosphoinositide hydrolysis and both basal and 5-HT-stimulated extracellular signal-regulated kinase 1͞2 phosphorylation are augmented in RSK2 knockout fibroblasts. Endogenous signaling by other GPCRs, including P2Y-purinergic, PAR-1-thrombinergic, ␤1-adrenergic, and bradykinin-B receptors, was also potentiated in RSK2-deficient fibroblasts. Importantly, reintroduction of RSK2 into RSK2؊͞؊ fibroblasts normalized signaling, thus demonstrating that RSK2 apparently modulates GPCR signaling by exerting a ''tonic brake'' on GPCR signal transduction. Our results imply the existence of a novel pathway regulating GPCR signaling, modulated by downstream members of the extracellular signal-related kinase͞ mitogen-activated protein kinase cascade. The loss of RSK2 activity in humans leads to Coffin-Lowry syndrome, which is manifested by mental retardation, growth deficits, skeletal deformations, and psychosis. Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, our results imply that alterations in GPCR signaling may account for some of its clinical manifestations.serotonin ͉ signal transduction G protein-coupled receptors (GPCRs) represent proximal molecular targets for most neurotransmitters, many psychiatric medications, and some drugs of abuse (1). Thus, for instance, antipsychotic and antidepressant medications interact with literally dozens of GPCRs (2). Drugs of abuse tend to have a more restricted pattern of interaction, with morphine being selective for -opioid receptors, and salvinorin A being selective for -opioid sites (3). GPCRs can also function as coreceptors for viruses; thus, the 5-hydroxytryptamine (5-HT) 2A serotonin receptor acts as a coreceptor for the JC virus, the agent responsible for progressive multifocal leukoencepalpathy (4). Agonist-induced activation of GPCRs frequently leads to a complex cascade of intracellular signaling involving arrestins and members of the mitogen-activated protein kinase (MAPK) cascade (5).The p90 ribosomal S6 kinases (RSK)1-4 are downstream members of the extracellular signal-regulated kinase (ERK)͞MAPK cascade, which contain two separate kinase domains connected by a linker domain (Fig. 1B) (6). Multiple phosphorylation events by upstream protein kinases are necessary for the complete activation of the N-terminal kinase (NTK) domain of RSKs (Fig. 1B). The NTK of RSK2 phosphorylates a broad range of substrates, including cAMP r...

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“…In addition to their classic interaction with heterotrimeric G-proteins, it is now recognized that GPCRs can interact with a wide range of functionally diverse proteins known collectively as 'GPCR interacting proteins' or 'GIPs', thereby regulating an array of other cellular events 103,104 . Furthermore, due to its divergent sequence and capacity to contain functionally distinct binding motifs, the intracellular C-tail domain of the GPCR is the critical binding domain for such interactions between GPCRs with their specific GIP(s) [103][104][105] .…”

Section: Regulation Of Ip Signalling Through Novel Protein:protein Inmentioning

confidence: 99%

“…Furthermore, due to its divergent sequence and capacity to contain functionally distinct binding motifs, the intracellular C-tail domain of the GPCR is the critical binding domain for such interactions between GPCRs with their specific GIP(s) [103][104][105] . To identify novel GIPs that interact with the IP, potentially shedding new insights into the role of prostacyclin within the vasculature including in cardioprotection, a yeast-two-hybrid (Y2H)-based screen of a human kidney cDNA library was carried out where the carboxyl (C)-terminal tail domain of the IP (IP 299-386 ) was used as the initial bait protein 96,97,106,107 .…”

Section: Regulation Of Ip Signalling Through Novel Protein:protein Inmentioning

confidence: 99%

Prostacyclin receptors: Transcriptional regulation and novel signalling mechanisms

Reid

Kinsella

2015

Prostaglandins & Other Lipid Mediators

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GPCR interacting proteins (GIP)

Cited by 245 publications

References 144 publications

Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release

Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release

p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling

Prostacyclin receptors: Transcriptional regulation and novel signalling mechanisms

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