scholarly journals Cannabinoid Receptor Interacting Protein 1a (CRIP1a): Function and Structure

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3672 ◽  
Author(s):  
William T. Booth ◽  
Noah B. Walker ◽  
W. Todd Lowther ◽  
Allyn C. Howlett
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Cannabinoid Receptor ◽  
Cb1 Receptor ◽  
Receptor Internalization ◽  
Receptor Interaction ◽  
Interacting Protein ◽  
Receptor Associated Protein ◽  
Metabotropic Glutamate ◽  
C Terminus

Cannabinoid receptor interacting protein 1a (CRIP1a) is an important CB1 cannabinoid receptor-associated protein, first identified from a yeast two-hybrid screen to modulate CB1-mediated N-type Ca2+ currents. In this paper we review studies of CRIP1a function and structure based upon in vitro experiments and computational chemistry, which elucidate the specific mechanisms for the interaction of CRIP1a with CB1 receptors. N18TG2 neuronal cells overexpressing or silencing CRIP1a highlighted the ability of CRIP1 to regulate cyclic adenosine 3′,5′monophosphate (cAMP) production and extracellular signal-regulated kinase (ERK1/2) phosphorylation. These studies indicated that CRIP1a attenuates the G protein signaling cascade through modulating which Gi/o subtypes interact with the CB1 receptor. CRIP1a also attenuates CB1 receptor internalization via β-arrestin, suggesting that CRIP1a competes for β-arrestin binding to the CB1 receptor. Predictions of CRIP1a secondary structure suggest that residues 34-110 are minimally necessary for association with key amino acids within the distal C-terminus of the CB1 receptor, as well as the mGlu8a metabotropic glutamate receptor. These interactions are disrupted through phosphorylation of serines and threonines in these regions. Through investigations of the function and structure of CRIP1a, new pharmacotherapies based upon the CRIP-CB1 receptor interaction can be designed to treat diseases such as epilepsy, motor dysfunctions and schizophrenia.

scholarly journals Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner

2016 ◽  
Vol 139 (3) ◽  
pp. 396-407 ◽  
Author(s):  
Lawrence C. Blume ◽  
Sandra Leone-Kabler ◽  
Deborah J. Luessen ◽  
Glen S. Marrs ◽  
Erica Lyons ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Cb1 Receptor ◽  
Receptor Internalization ◽  
Interacting Protein

Abstract 37: Nrip Deficiency Leads to Dilated Cardiomyopathy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Show-Li Chen
Keyword(s):  
Calcium Transient ◽  
Receptor Interaction ◽  
Cell Width ◽  
Interacting Protein ◽  
Cardiac Tissues ◽  
Calmodulin Binding ◽  
Calcineurin Phosphatase ◽  
And Function

Previously, we demonstrate a gene, nuclear receptor interaction protein (NRIP, also named DCAF6 or IQWD1) as a Ca2+- dependent calmodulin binding protein that can activate calcineurin phosphatase activity. Here, we found that α-actinin-2 (ACTN2), is one of NRIP-interacting proteins from the yeast two-hybrid system using NRIP as a prey. We further confirmed the direct bound between NRIP and ACTN2 using in vitro protein-protein interaction and in vivo co-immunoprecipitation assays. To further map the binding domain of each protein, the results showed the IQ domain of NRIP responsible for ACTN2 binding, and EF hand motif of ACTN2 responsible for NRIP bound. Due to ACTN2 is a biomarker of muscular Z-disc complex; we found the co-localization of NRIP and ACTN2 in cardiac tissues by immunofluorescence assays. Taken together, NRIP is a novel ACTN2-interacting protein. To investigate insights into in vivo function of NRIP, we generated conventional NRIP-null mice. The H&E staining results are shown in the hearts of NRIP KO mice are enlarged and dilated and the cell width of NRIP KO cardiomyocyte is increased. The EM of NRIP KO heart muscles reveal the reduction of I-band width and extension length of Z-disc in sarcomere structure; and the echocardiography shows the diminished fractional shortening in heart functions. Additionally, the calcium transient and sarcomere contraction length in cardiomyocytes of NRIP KO is weaker and shorter than wt; respectively. In conclusion, NRIP is a novel Z-disc protein and has function for maintenance of sarcomere integrity structure and function for calcium transient and muscle contraction.

scholarly journals The C Terminus of the Metabotropic Glutamate Receptor Subtypes 2 and 7 Specifies the Receptor Signaling Pathways

2001 ◽  
Vol 276 (49) ◽  
pp. 45800-45805 ◽  
Author(s):  
Julie Perroy ◽  
Gustavo J. Gutierrez ◽  
Vincent Coulon ◽  
Joel Bockaert ◽  
Jean-Pilippe Pin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtypes ◽  
Receptor Signaling ◽  
Metabotropic Glutamate ◽  
C Terminus

scholarly journals Mouse Receptor Interacting Protein 3 Does Not Contain a Caspase-Recruiting or a Death Domain but Induces Apoptosis and Activates NF-κB

1999 ◽  
Vol 19 (10) ◽  
pp. 6500-6508 ◽  
Author(s):  
Nanette J. Pazdernik ◽  
David B. Donner ◽  
Mark G. Goebl ◽  
Maureen A. Harrington
Keyword(s):  
Sequence Similarity ◽  
Kinase Domain ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Death Domain ◽  
Interacting Protein ◽  
C Terminus ◽  
Catalytically Active ◽  
Induced Apoptosis

ABSTRACT The death domain-containing receptor superfamily and their respective downstream mediators control whether or not cells initiate apoptosis or activate NF-κB, events critical for proper immune system function. A screen for upstream activators of NF-κB identified a novel serine-threonine kinase capable of activating NF-κB and inducing apoptosis. Based upon domain organization and sequence similarity, this novel kinase, named mRIP3 (mouse receptor interacting protein 3), appears to be a new RIP family member. RIP, RIP2, and mRIP3 contain an N-terminal kinase domain that share 30 to 40% homology. In contrast to the C-terminal death domain found in RIP or the C-terminal caspase-recruiting domain found in RIP2, the C-terminal tail of mRIP3 contains neither motif and is unique. Despite this feature, overexpression of the mRIP3 C terminus is sufficient to induce apoptosis, suggesting that mRIP3 uses a novel mechanism to induce death. mRIP3 also induced NF-κB activity which was inhibited by overexpression of either dominant-negative NIK or dominant-negative TRAF2. In vitro kinase assays demonstrate that mRIP3 is catalytically active and has autophosphorylation site(s) in the C-terminal domain, but the mRIP3 catalytic activity is not required for mRIP3 induced apoptosis and NF-κB activation. Unlike RIP and RIP2, mRIP3 mRNA is expressed in a subset of adult tissues and is thus likely to be a tissue-specific regulator of apoptosis and NF-κB activity. While the lack of a dominant-negative mutant precludes linking mRIP3 to a known upstream regulator, characterizing the expression pattern and the in vitro functions of mRIP3 provides insight into the mechanism(s) by which cells modulate the balance between survival and death in a cell-type-specific manner.

scholarly journals Design, Synthesis and Characterization of a New Series of Fluorescent Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulators

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1532
Author(s):  
Víctor Fernández-Dueñas ◽  
Mingcheng Qian ◽  
Josep Argerich ◽  
Carolina Amaral ◽  
Martijn D.P. Risseeuw ◽  
...  
Keyword(s):  
Binding Sites ◽  
Metabotropic Glutamate Receptor ◽  
Allosteric Modulators ◽  
Design Synthesis ◽  
Metabotropic Glutamate ◽  
Animal Disease Models ◽  
Fluorescent Ligands ◽  
The Brain

In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced neurotransmitter’ systems, thus providing safe and effective treatments for a number of central nervous system diseases. The metabotropic glutamate type 5 receptor (mGlu5R) has been shown to possess a druggable allosteric binding domain. Accordingly, novel allosteric ligands are being explored in order to finely regulate glutamate neurotransmission, especially in the brain. However, before testing the activity of these new ligands in the clinic or even in animal disease models, it is common to characterize their ability to bind mGlu5Rs in vitro. Here, we have developed a new series of fluorescent ligands that, when used in a new NanoBRET-based binding assay, will facilitate screening for novel mGlu5R allosteric modulators.

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