PMID- 24093505
OWN - NLM
STAT- MEDLINE
DCOM- 20140715
LR  - 20211021
IS  - 1756-6606 (Electronic)
IS  - 1756-6606 (Linking)
VI  - 6
DP  - 2013 Oct 5
TI  - HINT1 protein cooperates with cannabinoid 1 receptor to negatively regulate 
      glutamate NMDA receptor activity.
PG  - 42
LID - 10.1186/1756-6606-6-42 [doi]
AB  - BACKGROUND: G protein-coupled receptors (GPCRs) are the targets of a large number 
      of drugs currently in therapeutic use. Likewise, the glutamate ionotropic 
      N-methyl-D-aspartate receptor (NMDAR) has been implicated in certain neurological 
      disorders, such as neurodegeration, neuropathic pain and mood disorders, as well 
      as psychosis and schizophrenia. Thus, there is now an important need to 
      characterize the interactions between GPCRs and NMDARs. Indeed, these 
      interactions can produce distinct effects, and whereas the activation of 
      Mu-opioid receptor (MOR) increases the calcium fluxes associated to NMDARs, that 
      of type 1 cannabinoid receptor (CNR1) antagonizes their permeation. Notably, a 
      series of proteins interact with these receptors affecting their responses and 
      interactions, and then emerge as novel therapeutic targets for the aforementioned 
      pathologies. RESULTS: We found that in the presence of GPCRs, the HINT1 protein 
      influences the activity of NMDARs, whereby NMDAR activation was enhanced in 
      CNR1+/+/HINT1-/- cortical neurons and the cannabinoid agonist WIN55,212-2 
      provided these cells with no protection against a NMDA insult. NMDAR activity was 
      normalized in these cells by the lentiviral expression of HINT1, which also 
      restored the neuroprotection mediated by cannabinoids. NMDAR activity was also 
      enhanced in CNR1-/-/HINT1+/+ neurons, although this activity was dampened by the 
      expression of GPCRs like the MOR, CNR1 or serotonin 1A (5HT1AR). CONCLUSIONS: The 
      HINT1 protein plays an essential role in the GPCR-NMDAR connection. In the 
      absence of receptor activation, GPCRs collaborate with HINT1 proteins to 
      negatively control NMDAR activity. When activated, most GPCRs release the control 
      of HINT1 and NMDAR responsiveness is enhanced. However, cannabinoids that act 
      through CNR1 maintain the negative control of HINT1 on NMDAR function and their 
      protection against glutamate excitotoxic insult persists.
FAU - Vicente-Sanchez, Ana
AU  - Vicente-Sanchez A
AD  - Neuropharmacology, Instituto Cajal, CSIC, Madrid E-28002, Spain. 
      jgarzon@cajal.csic.es.
FAU - Sanchez-Blazquez, Pilar
AU  - Sanchez-Blazquez P
FAU - Rodriguez-Munoz, Maria
AU  - Rodriguez-Munoz M
FAU - Garzon, Javier
AU  - Garzon J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131005
PL  - England
TA  - Mol Brain
JT  - Molecular brain
JID - 101468876
RN  - 0 (Benzoxazines)
RN  - 0 (Hint1 protein, mouse)
RN  - 0 (Morpholines)
RN  - 0 (Naphthalenes)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Protein Subunits)
RN  - 0 (Receptor, Cannabinoid, CB1)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Receptors, Opioid, mu)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 5H31GI9502 
      ((3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
MH  - Animals
MH  - Benzoxazines/pharmacology
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology
MH  - Lentivirus/metabolism
MH  - Mice
MH  - Morpholines/pharmacology
MH  - N-Methylaspartate/toxicity
MH  - Naphthalenes/pharmacology
MH  - Nerve Tissue Proteins/deficiency/*metabolism
MH  - Neurons/drug effects/metabolism
MH  - Neuroprotective Agents/metabolism
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase Type I/metabolism
MH  - Protein Binding/drug effects
MH  - Protein Subunits/metabolism
MH  - Receptor, Cannabinoid, CB1/deficiency/*metabolism
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Receptors, Opioid, mu/metabolism
MH  - Zinc/metabolism
PMC - PMC3851374
EDAT- 2013/10/08 06:00
MHDA- 2014/07/16 06:00
PMCR- 2013/10/05
CRDT- 2013/10/08 06:00
PHST- 2013/08/22 00:00 [received]
PHST- 2013/09/19 00:00 [accepted]
PHST- 2013/10/08 06:00 [entrez]
PHST- 2013/10/08 06:00 [pubmed]
PHST- 2014/07/16 06:00 [medline]
PHST- 2013/10/05 00:00 [pmc-release]
AID - 1756-6606-6-42 [pii]
AID - 10.1186/1756-6606-6-42 [doi]
PST - epublish
SO  - Mol Brain. 2013 Oct 5;6:42. doi: 10.1186/1756-6606-6-42.