Biology subjects

Jimenez-Diaz, L.

Publications and source records attributed to Jimenez-Diaz, L..

7 recordsLinked to original sources

bioRxiv2025

Structure-based identification of GIRK2-PIP2 modulators among known drugs and metabolites using docking, MM-GBSA, ADMET, and molecular dynamics

G protein-gated inwardly rectifying potassium (GIRK) channels are key regulators of neuronal excitability, making them promising therapeutic targets for central nervous system disorders. Their activation depends on phosphatidylinositol-4,5-bisphosphate (PIP2), which stabilizes the channels open state. A deeper understanding of GIRK-PIP2 interactions could uncover new physiological roles and pave the way for therapies that modulate channel function. This study aimed to advance the targeting of GIRK channels at the PIP2-binding site. Over one million compounds were screened against GIRK2 (PDB ID: 4KFM) using high-throughput virtual screening. A core constraint with a root-mean-square deviation (RMSD) < 2 [A] was applied to assure the accuracy and binding close to PIP2-binding site. The top-scoring ligands were redocked with Glide (SP, XP) and binding free energy was estimated using Molecular Mechanics Generalized Born Surface Area method. The most promising compounds were analyzed for pharmacokinetic/physicochemical properties, followed by molecular dynamics (MD) simulations over 200 ns in membrane bilayer. MD analysis revealed three known compounds (Rosuvastatin, CID: 54365126 and 7304563) as potential competitive GIRK2 modulators, exhibiting stable interactions with residues critical for binding endogenous activators (PIP2, cholesterol), and GIRK-acting drugs. Docking analyses also revealed strong binding to GIRK2 for various metabolites, including leukotrienes, resolvins, acyl-CoAs, and polyphosphates, including adenosine-triphosphate (ATP) and thiamine-triphosphate. Notably, some of the identified compounds can affect similar ion channels, indicating potential cross-reactivity with GIRK2. Furthermore, the binding modes of acyl-CoAs and polyphosphates closely resemble PIP2s hydrophobic and phosphate group engagement. Together, these findings offer promising candidates for experimental validation and therapeutic development. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/653795v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1325e66org.highwire.dtl.DTLVardef@1d3835corg.highwire.dtl.DTLVardef@1550df3org.highwire.dtl.DTLVardef@107007e_HPS_FORMAT_FIGEXP M_FIG C_FIG Abbreviations: ADMET - Absorption, Distribution, Metabolism, Elimination, Toxicity; CID - PubChem Compound Identification; MM-GBSA - Molecular Mechanics with Generalized Born and Surface Area solvation; RMSD - Root-Mean-Square Deviation; SP - Standard Precision; PIP2 - phosphatidylinositol-4,5-bisphosphate; XP - Extra Precision. HIGHLIGHTSO_LIMulti-target screening identifies selective modulators of the GIRK2 channel C_LIO_LILigands target the PIP2-binding site, a novel interface for GIRK2 modulation C_LIO_LIMM-GBSA confirms binding affinity and ligand stability post-docking C_LIO_LIDynamics and bioinformatics predict selectivity and off-target interactions C_LIO_LIStatins and leukotriene-modifying drugs are strong GIRK2 modulator candidates C_LI

bioinformatics↗

bioRxiv2024

Low dose of a non-urea selective GIRK channel activator improves hippocampal-dependent synaptic plasticity and memory disrupted by amyloid-β oligomers

Increased neural activity characterizes early Alzheimers disease (AD), serving as a prognostic indicator for disease progression and cognitive decline. Mechanisms that drive this hyperactivity and their behavioral effects remain mostly unrevealed, although normalizing altered excitability levels has been shown to reverse cognitive impairment in early AD, both in animals and humans. Soluble amyloid-{beta} oligomers (oA{beta}) primary accumulate in limbic regions like hippocampus and induce neuronal hyperexcitability and subsequent cognitive deficits by impairing ion channels function. Indeed, G protein-gated inwardly rectifying K+ (GIRK) channels -that control neuronal excitability-are greatly affected and their selective pharmacological activation has already been shown very effective to counteract oA{beta}-induced hyperexcitability and hippocampal dysfunction. However, GIRK gain-of-function in healthy animals disrupts learning, memory and underlying synaptic plasticity, greatly limiting its therapeutic potential in preclinical asymptomatic early AD patients. Therefore, GIRK-based pharmacological treatment needs further investigation to overcome these limitations. Here we tested two doses of a novel, more potent, and neuronal selective GIRK activator, VU0810464, in healthy and early oA{beta}1-42-generated AD male and female mice. Both doses normalized hippocampal synaptic plasticity (long-term potentiation, LTP) and associated spatial object location memory (OLM) without sex dimorphism in AD animals. However, in healthy mice, low VU0810464 dose did not significantly alter LTP and OLM, whereas the high dose disrupted both. Our results suggest that the precise tuning of neural excitability with low dosing of VU0810464 might be a promising strategy to safely treat and prevent hippocampal overexcitation and upstreaming memory deficits in early preclinical asymptomatic phases of AD.

neuroscience↗

bioRxiv2024

Mapping the spatial proteomic signature of dorsal and ventral hippocampus in a mouse model of early Alzheimer's disease: changes in synaptic plasticity-related proteins associated with sexual dimorphism

BackgroundAn initial neuropathological hallmark of Alzheimers disease (AD) is the hippocampal dysfunction caused by amyloid-{beta} (A{beta}) peptides accumulation. Soluble oligomeric forms of A{beta} shift synaptic plasticity induction threshold leading to memory deficits in male and female mice in early amyloidosis models. Some protein changes underlying those deficits have been previously studied, but the spatial distribution within the hippocampus, as well as the potential sex differences, remain unknown. Since each hippocampal region (dorsal vs. ventral) has clearly distinct functionality and connectivity, we postulated that some protein changes may be unique to each and might also be sex-dependent. MethodsAn innovative spatial proteomics study was performed to map whole hippocampal proteome distribution using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry, which allows protein detection with spatial resolution directly on tissue sections. Brains from sixteen adult male and female mice intracerebroventricularly injected with A{beta}1-42 oligomers or vehicle were sectioned. MALDI imaging was performed using a RapifleXTM MALDI TissuetyperTM TOF/TOF mass spectrometer followed by protein identification by traditional tandem mass spectrometry (MS/MS) directly on the tissue. To precisely delineate both dorsal and ventral hippocampus, a Nissl staining was performed on succeeding tissue sections. ResultsOf the 234 detected peptides, significant differences in expression levels were found in 34 proteins, due to treatment, sex, or hippocampal location. Moreover, a significant protein-protein interaction (PPI) was observed, showing a relationship to long-term potentiation (LTP), the functional basis of memory. Accordingly, 14 proteins related to synaptic plasticity and/or AD were selected to further study. Results showed many of the altered protein to modulate glycogen synthase kinase-3{beta} (GSK-3{beta}), a protein widely involved in the regulation of synaptic plasticity induction threshold. In fact, hippocampal GSK-3{beta} was found overactivated suggesting a facilitated long-term depression (LTD) instead of LTP in AD models. ConclusionsThis study offers for the first time the specific protein changes in dorsal/ventral hippocampus in both male and female mice, that modulate GSK-3{beta} activity, providing new insight in the pathogenesis of early AD and valuable potential biomarkers for early diagnosis and therapeutic targets.

neuroscience↗

bioRxiv2024

BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE

The ketogenic diet, characterized by high fat and low carbohydrates, has gained popularity not only as a strategy for managing body weight but also for its efficacy in delaying cognitive decline associated with neurodegenerative diseases and the aging process. Since this dietary approach stimulates the livers production of ketone bodies, primarily {beta}-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons, we investigated whether BHB could mitigate impaired AMPA receptor trafficking, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as saturated fatty acids. Here, we observe that, in cultured primary cortical neurons, exposure to palmitic acid (200M) decreased surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids, such as oleic acid and {omega}-3 docosahexaenoic acid (200M), and BHB (5mM) increased them. Furthermore, BHB countered the adverse effects of palmitic acid on synaptic GluA1 levels in hippocampal neurons, as well as excitability and plasticity in hippocampal slices. Additionally, daily intragastric administration of BHB (100 mg/kg/day) for two months reversed cognitive impairment induced by a saturated high-fat diet (49% of calories from fat) in a mouse experimental model of obesity. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptors abundance, synaptic function and neuroplasticity, shedding light on the potential use of BHB to delay cognitive impairments associated with metabolic diseases.

neuroscience↗

bioRxiv2023

Impairments in hippocampal oscillations accompany the loss of LTP induced by GIRK activity blockade

Learning and memory occurrence requires of hippocampal long-term synaptic plasticity and a precise neural activity orchestrated by brain network oscillations, both processes reciprocally influencing each other. As G-protein-gated inwardly rectifying potassium (GIRK) channels rule synaptic plasticity that supports hippocampal-dependent memory, here we assessed their unknown role in hippocampal oscillatory activity in relation to synaptic plasticity induction. In alert male mice, pharmacological GIRK modulation did not alter neural oscillations before long-term potentiation (LTP) induction. However, after an LTP generating protocol, both gain- and loss-of basal GIRK activity transformed LTP into long-term depression, but only specific suppression of constitutive GIRK activity caused a disruption of network synchronization ({delta}, , {gamma} bands), even leading to long-lasting ripples and fast ripples pathological oscillations. Together, our data showed that constitutive GIRK activity plays a key role in the tuning mechanism of hippocampal oscillatory activity during long-term synaptic plasticity processes that underlies hippocampal-dependent cognitive functions.

neuroscience↗

bioRxiv2022

Spatial memory training reverses GirK channels modulation in the transgenic APPSw,Ind Alzheimer's disease mouse model

Alzheimers disease (AD) is a dementia characterized by progressive memory decline and neurodegeneration caused by the accumulation of amyloid-{beta} (A{beta}) peptides. Last findings point to an imbalance between excitatory and inhibitory neurotransmission as the initial impairment in early stages, and the hippocampus as one of the most susceptible brain areas. The G-protein-gated inwardly rectifying potassium (GirK) channel has been proposed as a potential target to restore excitatory/inhibitory balance in amyloidosis models. Moreover, cognitive training may counteract early AD symptoms, although its effect on GirK channels remains unknown. Here, the effect of genotype, age, and training in a hippocampal-dependent memory task on the protein expression of GirK subunits and modulators were studied using APPSw,Ind mice. Results showed a reduction of GirK2 expression as well as an increased expression of SNX27 in the hippocampus of 6-month-old APPSw,Ind mice. Training in a memory task restored GirK2 and SNX27 levels. Thus, the effect of A{beta} on GirK2 could account for the excitatory/inhibitory imbalance transmission found in AD models, and training in a cognitive hippocampal-dependent task reverses this effect and lessens early A{beta}-dependent AD deficits. Summary statementA{beta} decreases hippocampal GirK2 expression in APPSw,Ind mice, which could contribute to early hyperexcitability found in Alzheimers disease models. Training in spatial memory tasks has shown to counteract this reduction.

neuroscience↗

bioRxiv2020

Basal G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels activity governs synaptic plasticity that supports dorsal hippocampus-dependent cognitive functions

G-protein-gated inwardly rectifying potassium (Kir3/GirK) channel is the effector of many G-protein-coupled receptors. Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimers and Parkinsons diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. GirK channels are constitutively activated in the dorsal hippocampus contributing to resting membrane potential, and their synaptic activation compensates any excitation excess. Here, in order to elucidate the role of GirK channels activity in the maintenance of dorsal hippocampus-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined. For that purpose, basal GirK activity was pharmacologically modulated by two specific drugs: ML297, a GirK channel opener, and Tertiapin-Q, a GirK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied pharmacological GirK modulation effect on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular injections of both GirK modulators to study their contribution to CA3-CA1 synapse electrophysiological properties, synaptic plasticity, and learning and memory capabilities during hippocampal dependent tasks. We found that pharmacological disruption of basal GirK activity in dorsal hippocampus, causing either function gain or loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GirK activity must take place in the hippocampus to sustain cognitive functions. Significance StatementThe dorsal hippocampus mostly performs cognitive functions related to contextual/spatial associations. These functions rely on synaptic plasticity processes that are critically ruled by a finely tuned neural excitability. Being the downstream physiological effectors of a variety of G-coupled receptors, activation of G protein-gated inwardly rectifying K+ (GirK) channels induces neurons to hyperpolarize, contributing to neural excitability throughout the control of excitatory excess. Here, we demonstrate that modulation of basal GirK channels activity, causing either function gain or loss, transforms HFS-induced LTP into LTD, inducing deficits in dorsal hippocampus-dependent learning and memory. Together, our data show a crucial GirK activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.

neuroscience↗