PXD013328

PXD013328 is an original dataset announced via ProteomeXchange.

Title	Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-protein interaction networks
Description	Ligand-dependent differences in the regulation and internalization of the mu-opioid receptor (MOR) have been linked to the degree of severity of the side effects that limit the use of opiates in the treatment of pain. For example, activation of the MOR by morphine and DAMGO ([D-Ala2,N-MePhe4,Gly-ol]-enkephalin) causes distinct patterns of spatiotemporal signaling which are dependent on the distribution pattern of the receptor at the plasma membrane after activation. Morphine stimulation of MOR activates a Gβγ-protein kinase C (PKC)α-phosphorylation pathway that limits the distribution of the MOR and is associated with a sustained increase in cytosolic extracellular signal regulated kinase (ERK). In contrast, DAMGO causes a redistribution of the MOR at the plasma membrane (prior to receptor internalization), that facilitates transient activation of cytosolic and nuclear ERK. Here, we use proximity biotinylation proteomics to dissect the different protein-interaction networks that underlie the spatiotemporal signaling of morphine and DAMGO. We found that DAMGO, but not morphine, activates Rac1 (Ras‐related C3 botulinum toxin substrate 1). Rac1 activation is dependent on the scaffolding proteins IQ motif-containing GTPase-activating protein-1 (IQGAP1) and Crk-like protein (CRKL), and CRKL is required for the transient increase in nuclear ERK. In contrast, morphine increased the proximity of the MOR to desmosomes, specialized and highly-ordered membrane domains. Knockdown of desmosomal proteins junction plakoglobin (JUP) or desmocolin-1 (DSC1) switched the morphine spatiotemporal signaling profile to mimic that of DAMGO, revealing a transient increase in nuclear ERK. Identifying the MOR-interaction networks that control differential spatiotemporal signaling represents an important step towards understanding how signal compartmentalization contributes to the development of tolerance and dependence.
HostingRepository	PRIDE
AnnounceDate	2019-09-26
AnnouncementXML	Submission_2019-09-26_00:22:02.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Srgjan Chivchiristov
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	biotinylated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-04-01 05:19:45	ID requested
⏵ 1	2019-09-26 00:24:53	announced

Civciristov S, Huang C, Liu B, Marquez EA, Gondin AB, Schittenhelm RB, Ellisdon AM, Canals M, Halls ML, -opioid receptor are controlled by distinct protein-interaction networks. J Biol Chem, 294(44):16198-16213(2019) [pubmed]

submitter keyword: G protein-coupled receptor (GPCR), opioid, cell compartmentalization, protein complex, proteomics, extracellular signal regulated kinase (ERK), desmosome, Ras‐related C3 botulinum toxin substrate 1 (Rac1)

Michelle Louise Halls
contact affiliation	Drug Discovery Biology Theme Monash Institute of Pharmaceutical Sciences Monash University 399 Royal Parade (Mail address: 381 Royal Parade) Parkville VIC 3052 Australia
contact email	michelle.halls@monash.edu
lab head
Srgjan Chivchiristov
contact affiliation	Monash University, Melbourne
contact email	srgjan.chivchiristov@monash.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013328
     1. Label: PRIDE project
     2. Name: Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-protein interaction networks