CRIP1a switches cannabinoid receptor agonist/antagonist-mediated protection from glutamate excitotoxicity

doi:10.1016/j.neulet.2011.08.041

Neuroscience Letters

Volume 503, Issue 3, 10 October 2011, Pages 224-228

https://doi.org/10.1016/j.neulet.2011.08.041 Get rights and content

Abstract

A shared pathology among many neurological and neurodegenerative disorders is neuronal loss. Cannabinoids have been shown to be neuroprotective in multiple systems. However, both agonists and antagonists of the CB₁ cannabinoid receptor are neuroprotective, but the mechanisms responsible for these actions remain unclear. Recently a CB₁ receptor interacting protein, CRIP1a, was identified and found to alter CB₁ activity. Here we show that in an assay of glutamate neurotoxicity in primary neuronal cortical cultures CRIP1a disrupts agonist-induced neuroprotection and confers antagonist-induced neuroprotection.

Highlights

► CB₁ is expressed in embryonic cortical neurons in vitro and in vivo. ► CRIP1a mRNA and protein are expressed in cortical neurons in vitro and in vivo. ► CRIP1a, CB₁ agonist, and CB₁ antagonist did not alter basal neuronal cell death. ► CRIP1a reversed CB₁ agonist mediated neuroprotection from glutamate excitotoxicity. ► CRIP1a conferred to a CB₁ antagonist neuroprotection from glutamate excitotoxicity.

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Cited by (13)

Cell signaling of the CB<inf>1</inf> cannabinoid receptor via β-arrestins, cannabinoid receptor interacting protein (CRIP1a) and other regulatory proteins
2023, Cannabis Use, Neurobiology, Psychology, and Treatment
The CB₁ cannabinoid receptor (CB₁R) is associated with proteins that regulate cellular signaling responses to endocannabinoids 2-arachidoylglycerol and anandamide, the phytocannabinoid Δ⁹-tetrahydrocannabinol, and other agonists (CP55940, WIN55212-2). CB₁Rs activate heterotrimeric G proteins (predominantly Gi/o), allowing Giα-GTP and Gβγ to direct initial cellular signaling. Regulators of G protein signaling (RGS) proteins facilitate inactivation of Gαi by hydrolysis of GTP to GDP. G protein-coupled receptor kinases phosphorylate CB₁Rs. This promotes binding of β-arrestins1 and 2, which scaffold to alternative cellular signaling proteins or clathrin for internalization. Cannabinoid receptor interacting protein1a (CRIP1a) binds Gαi and attenuates signaling and competes with β-arrestins1 and 2 for the CB₁R. Proteins that regulate CB₁R intracellular trafficking include binding protein (BiP), SH3 domain GRB2-like (endothelin) interacting protein1 (SGIP1), Wntless/GPR177 (WLS), and G protein-coupled receptor-associated sorting protein1 (GASP1). Failure of these associated proteins to function in signal transduction or the CB₁R life cycle contributes to disease states.
The Protein-Protein Interactions of Cannabinoid Receptor Interacting Protein 1a (CRIP1a) and Cannabinoid 1 Receptor: The Molecular Mechanism Study Through an Integrated Molecular Modeling Approach
2017, Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis, and Treatment
One of the key regulators unique to cannabinoid receptors are the cannabinoid receptor interacting proteins (CRIPs). Among them, CRIP1a was found to decrease the constitutive activity of the cannabinoid type-1 receptor (CB₁R). The aim of this chapter is to report the application of different computational techniques to gain an understanding of the interaction between CRIP1a and CB₁R. This was achieved by utilizing three different methods to build a model for the CRIP1a protein, namely: comparative modeling, ab initio, and protein threading. The best fitting model (built using RhoGDI 2 as a template) was docked to the C-terminus of CB₁R. The docked model was then subjected to a 10 ns all-atom molecular dynamics simulation in an explicit solvent system, for refinement. The final model putatively demonstrated several key interactions between CRIP1a and CB₁R, including those involving Lys130 of CRIP1a.
Cannabinoid receptor interacting protein (CRIP1a) attenuates CB<inf>1</inf>R signaling in neuronal cells
2015, Cellular Signalling
Citation Excerpt :
Our data demonstrate that neither gene expression nor total cellular protein levels of CB1R are altered by changing the level of CRIP1a expression, and that protein synthesis inhibition does not change CB1R plasma membrane density in CRIP1a XS or KD cells. Using stable and transient over-expression of CRIP1a, we and other laboratories and us have shown that CRIP1a had no effect on total CB1R protein expression using other models [1,13,17]. These findings suggest that plasma membrane CRIP1a localization is not dependent on CB1R de novo synthesis.
CB₁ cannabinoid receptors (CB₁R) are one of the most abundantly expressed G protein coupled receptors (GPCR) in the CNS and regulate diverse neuronal functions. The identification of GPCR interacting proteins has provided additional insight into the fine-tuning and regulation of numerous GPCRs. The cannabinoid receptor interacting protein 1a (CRIP1a) binds to the distal carboxy terminus of CB₁R, and has been shown to alter CB₁R-mediated neuronal function [1]. The mechanisms by which CRIP1a regulates CB₁R activity have not yet been identified; therefore the focus of this investigation is to examine the cellular effects of CRIP1a on CB₁R signaling using neuronal N18TG2 cells stably transfected with CRIP1a over-expressing and CRIP1a knockdown constructs. Modulation of endogenous CRIP1a expression did not alter total levels of CB₁R, ERK, or forskolin-activated adenylyl cyclase activity. When compared to WT cells, CRIP1a over-expression reduced basal phosphoERK levels, whereas depletion of CRIP1a augmented basal phosphoERK levels. Stimulation of phosphoERK by the CB₁R agonists WIN55212-2, CP55940 or methanandamide was unaltered in CRIP1a over-expressing clones compared with WT. However, CRIP1a knockdown clones exhibited enhanced ERK phosphorylation efficacy in response to CP55940. In addition, CRIP1a knockdown clones displayed a leftward shift in CP55940-mediated inhibition of forskolin-stimulated cAMP accumulation. CB₁R-mediated G_i3 and G_o activation by CP99540 was attenuated by CRIP1a over-expression, but robustly enhanced in cells depleted of CRIP1a. Conversely, CP55940-mediated G_i1 and G_i2 activation was significant enhanced in cells over-expressing CRIP1a, but not in cells deficient of CRIP1a. These studies suggest a mechanism by which endogenous levels of CRIP1a modulate CB₁R-mediated signal transduction by facilitating a G_i/o protein subtype preference for G_i1 and G_i2, accompanied by an overall suppression of G-protein-mediated signaling in neuronal cells.
Predicting the molecular interactions of CRIP1a-cannabinoid 1 receptor with integrated molecular modeling approaches
2014, Bioorganic and Medicinal Chemistry Letters
Cannabinoid receptors are a family of G-protein coupled receptors that are involved in a wide variety of physiological processes and diseases. One of the key regulators that are unique to cannabinoid receptors is the cannabinoid receptor interacting proteins (CRIPs). Among them CRIP1a was found to decrease the constitutive activity of the cannabinoid type-1 receptor (CB₁R). The aim of this study is to gain an understanding of the interaction between CRIP1a and CB₁R through using different computational techniques. The generated model demonstrated several key putative interactions between CRIP1a and CB₁R, including the critical involvement of Lys130 in CRIP1a.
SGIP1 in axons prevents internalization of desensitized CB1R and modifies its function
2023, Frontiers in Neuroscience
Cannabinoid receptor interacting protein 1a (CRIP1a) in health and disease
2020, Biomolecules

View all citing articles on Scopus

^☆: This work was funded by the PSRP, MCGRI, to DLL and LRH.

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CRIP1a switches cannabinoid receptor agonist/antagonist-mediated protection from glutamate excitotoxicity☆

Abstract

Highlights

Neurosci. Lett.

Neurobiol. Dis.

Neuroscience

Neuroscience

Neuron

Neuroscience

Neuropharmacology

Massive accumulation of N-acylethanolamines after stroke. Cell signaling in acute cerebral ischemia?

J. Neurochem.

Localization of mRNA expression and activation of signal transduction mechanisms for cannabinoid receptor in rat brain during fetal development

Development

Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease

Brain

Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length

J. Neurosci.

Self-inactivating lentiviral vectors with enhanced transgene expression as potential gene transfer system in Parkinson's disease

Hum. Gene Ther.

Woodchuck hepatitis virus contains a tripartite posttranscriptional regulatory element

J. Virol.

Δ9-Tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurons via activation of the CB1 receptor

NeuroReport

Localisation of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal tail of CB1

J. Comp. Neurol.

AAV vector-mediated overexpression of CB1 cannabinoid receptor in pyramidal neurons of the hippocampus protects against seizure-induced excitotoxicity

PloS One

Δ⁹-Tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurons via activation of the CB₁ receptor

Localisation of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal tail of CB₁