Biology subjects

Langiu, M.

Publications and source records attributed to Langiu, M..

3 recordsLinked to original sources

bioRxiv2024

Pharmacological characterisation of allosteric modulators at human mGlu5

The metabotropic glutamate receptor 5 (mGlu5) is a Class C G protein-coupled receptor, ubiquitously expressed throughout the CNS. With major roles in cognition, learning and memory, mGlu5 dysfunction is linked with numerous neurodegenerative and neuropsychiatric disorders, presenting a viable therapeutic target. Allosteric modulators bind topographically distinct sites from glutamate and other orthosteric agonists and enhance (positive allosteric modulators, PAMs), inhibit (negative allosteric modulators, NAMs) or do not effect (neutral allosteric ligands, NALs) mGlu5 function. While mGlu5 modulators have efficacy in in vivo rodent models of CNS disorders, none have made it to the clinic. We hypothesise this lack of translatability is arises from preclinical optimisation using on non-human pharmacological data, as functional studies are predominantly performed using rat mGlu5 and non-human brain neuronal cultures. Here we assess and quantify the impact of eleven chemically and pharmacologically diverse mGlu5 PAMs, NAMs and NALs on human mGlu5 activity using radioligand binding, iCa2+ mobilisation and IP1 accumulation assays. By comparing to published and newly generated data for rat mGlu5 we show that while modulator pharmacology is relatively consistent across species, ligand dependent species differences in allosteric modulator affinity, cooperativity and probe dependence are evident. Additionally, we report PAM-dependent effects on orthosteric agonist kinetic profiles at human mGlu5. Together, these data highlight the importance of systematic evaluation of mGlu5 allosteric ligand activity at human mGlu5 to improve drug design and overcome potential barriers to translatability to clinical settings.

pharmacology and toxicology↗

bioRxiv2024

Consequences of platelet-educated cancer cells on the expression of inflammatory and metastatic glycoproteins.

Cancer-associated thrombosis, a major cause of mortality in cancer patients, exhibits a 4 to 7 times higher incidence compared to the general population. Platelet activation by tumor cells contributes to this pro-thrombotic state. Cancer cell-educated platelets have also been described to be implicated in promoting metastasis. Intriguingly, our team, among others, unveils a reverse process, wherein platelets educate cancer cells by transferring lipids, RNAs, and proteins. Here, focusing on colorectal and pancreatic cancers, our study investigates genes and proteins mediating platelet education of cancer cells. We demonstrated, for the first time, that platelets can educate cancer cells by inducing changes in the transcription of genes related to glycosylation, inflammation, and metastasis in cancer cells themselves. These results indicate a direct impact of platelets on cancer cell phenotype. This novel insight suggests potential therapeutic avenues for cancer treatment, disrupting platelet-mediated alterations and influencing the course of cancer progression.

cancer biology↗

bioRxiv2022

Gpr88 deletion impacts motivational control independently of striatal dopamine function

BackgroundDisrupted motivational control is a common--but poorly treated--feature of psychiatric disorders. Aberrant mesolimbic dopamine signalling is implicated in motivational symptoms, however direct manipulations to these pathways have yielded suboptimal therapeutic effects. GPR88 is an orphan G protein-coupled receptor highly expressed in the striatum on medium spiny neurons, and therefore well-placed to modulate striatal signalling. While the phenotype of Gpr88 knockout mice supports a disruption of motivational pathways, it is unclear whether GPR88 is involved in reward valuation and/or effort-based decision making in a sex-dependent manner, and if this involves altered dopamine function. MethodsIn male and female Gpr88 knockout mice, we used touchscreen-based progressive ratio, with and without reward devaluation, and effort-related choice tasks to assess motivation and cost/benefit decision making, respectively. To explore whether these motivational behaviours were related to altered striatal dopamine, we quantified expression of dopamine-related genes and/or proteins, and used [18F]DOPA PET and GTP{gamma}[35S] binding to assess pre- and postsynaptic dopamine function, respectively. ResultsWe show that male and female Gpr88 knockout mice display greater motivational drive than wild-type mice, which was maintained following reward devaluation. Further, we show that cost/benefit decision making is impaired in male, but not female, Gpr88 knockout mice. Surprisingly, we found that Gpr88 deletion had no effect on striatal dopamine by any of the measures assessed. ConclusionOur results highlight that GPR88 regulates motivational control of behaviour through a dopaminergic-independent mechanism, providing further support for GPR88 as target for mood symptoms in psychiatric disorders.

neuroscience↗