Biology subjects

Andres, M. E.

Publications and source records attributed to Andres, M. E..

5 recordsLinked to original sources

bioRxiv2026

Individual differences in novelty-seeking behavior are modulated by GRK2/3 inhibition in rats

Background and Purpose High novelty-seeking is an endophenotype associated with greater vulnerability to drug addiction, marked by a hyperdopaminergic state and reduced dopamine D2 receptor (D2R) levels in the dorsal striatum (DS). G protein-coupled receptor kinases (GRKs) regulate desensitization, internalization, and recycling of these receptors, including the D2R. This study investigated the relevance of GRK2 and 3 (GRK2/3) in novelty-seeking behavior and striatal dopamine dynamics. Experimental Approach Individual novelty-seeking trait was assessed in Sprague Dawley rats using an open-field test. D2R, GRK2, and GRK5 protein levels were measured in synaptosomal DS samples using Western Blot. Pharmacological inhibition of GRK2/3 was assessed using Cmpd101. We tested the effect of systemic Cmpd101 administration on contextual novelty discrimination and local Cmpd101 perfusion on baseline and stimulus-evoked extracellular dopamine (DA) levels in the DS. Key Results Locomotor activity in a novel environment inversely correlated with the synaptosomal GRK2 and D2R protein levels in the DS. Systemic Cmpd101 treatment modulated the locomotor discrimination index in a novelty phenotype-dependent manner. Moreover, local Cmpd101 perfusion in the DS elicited a sustained elevation in basal extracellular dopamine levels and significantly blunted subsequent stimulus-evoked DA release, both effects independent of novelty-seeking phenotype. Conclusion and Implications Together, our findings link GRK2/3 signaling to individual differences in novelty-seeking and striatal dopaminergic function. These results suggest a potential relevance to drug addiction vulnerability.

neuroscience↗

bioRxiv2020

Bioinformatics approach reveals Nur77-regulated genes common to the central nervous and immune systems

Neurons and immune cells have similar mechanisms for cell to cell communication. Exists active crosstalk between neurons and immune cells. Neurotransmitters can activate or inhibit immune cells, and cytokines modulate neuronal activity. The transcription factor Nur77 (NR4A1) is highly and transiently induced by several stimuli in neurons and T-lymphocytes, suggesting that Nur77 is involved in the coordination of the genetics response in both cell types. By analyzing publicly available databases, we found Nur77 target genes common to the nervous and immune systems. Functions as cell adhesion and anchoring appear as processes regulated by Nur77 in neurons and immune cells.

neuroscience↗

bioRxiv2020

MicroExonator enables systematic discovery and quantification of microexons across mouse embryonic development

Microexons, exons that are [≤]30 nucleotides, were shown to play key roles in neuronal development, but are difficult to detect and quantify using standard RNA-Seq alignment tools. Here, we present MicroExonator, a novel pipeline for reproducible de novo discovery and quantification of microexons. We processed 289 RNA-seq datasets from eighteen mouse tissues corresponding to nine embryonic and postnatal stages, providing the most comprehensive survey of microexons available for mouse. We detected 2,984 microexons, 332 of which are differentially spliced throughout mouse embryonic brain development, including 29 that are not present in mouse transcript annotation databases. Unsupervised clustering of microexons alone segregates brain tissues by developmental time and further analysis suggest a key function for microexon inclusion in axon growth and synapse formation. Finally, we analysed single-cell RNA-seq data from the mouse visual cortex and we report differential inclusion between neuronal subpopulations, suggesting that some microexons could be cell-type specific.

genomics↗

bioRxiv2019

Presence of a D2 receptor truncated protein in the brain of the D2 receptor functional knockout mouse, revisiting its molecular and neurochemical features

Null mice for the dopamine D2 receptor (D2R) have been instrumental in understanding the function of this protein in the central nervous system. Several lines of D2R knockout mice have been generated, which share some characteristics but differ in others. The D2R functional knockout mouse, first described in 1997, is functionally null for D2R-mediated signaling but the Drd2 gene was interrupted at the most extreme distal end leaving open the question about whether transcript and protein are produced. We decided to determine if there are D2R transcripts, the characteristics of these transcripts and whether they are translated in the brain of D2R functional knockout mice. Sequence analysis of 3 Rapid Amplification of cDNA Ends showed that D2R functional knockout mice express transcripts that lack only the exon eight. Immunofluorescence showed D2R-like protein in the brain of the knockout mice. As previously reported, D2R functional knockout mice are hypoactive and insensitive to the D2R agonist quinpirole (QNP). However, the heterozygous showed locomotor activity and response to QNP similar to the wild-type mice. Intriguingly, microdialysis experiments showed that heterozygous mice, such as knockouts, have half the normal levels of synaptic dopamine in the striatum. However, heterozygous mice responded similarly to wild-type mice to an acute injection of QNP, showing a 50% decrease in synaptic dopamine. In conclusion, D2R functional knockout mice express transcripts that lead to a truncated D2R protein that lacks from the sixth transmembrane domain to the C-terminal end but retains the third intracellular loop. We discuss the implications of this truncated D2R coexisting with the native D2R that may explain the unexpected outcomes observed in the heterozygous. Finally, we suggest that the D2R functional knockout mouse can be a useful model for studying protein-protein interaction and trafficking of D2R.

neuroscience↗

bioRxiv2019

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

NR4A is a nuclear receptor protein family whose members act as sensors of cellular environment and regulate multiple processes such as metabolism, proliferation, migration, apoptosis, and autophagy. Since the ligand binding domains of these receptors have no cavity for ligand interaction, their function is most likely regulated by protein abundance and post-translational modifications. In particular, NR4A1 is regulated by protein abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic translocation), and acts both as a transcription factor and as a regulator of other interacting proteins. SUMOylation is a post-translational modification that can affect protein stability, transcriptional activity, alter protein-protein interactions and modify intracellular localization of target proteins. In the present study we evaluated the role of SUMOylation as a posttranslational modification that can regulate the activity of NR4A1 to induce autophagy-dependent cell death. We focused on a model potentially relevant for neuronal cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic cell death. We observed that a triple mutant in SUMOylation sites has reduced SUMOylation, increased transcriptional activity, altered intracellular distribution, and more importantly, its ability to induce autophagic cell death is impaired.\n\nSummary StatementThe modification of the nuclear receptor NR4A1 by SUMO regulates its transcriptional activity, intracellular localization and is required to induce autophagic cell death.

biochemistry↗