Gβγ subunit inhibitor decreases DOM-induced head twitch response via the PLCβ/IP3/Ca2+/ERK and cAMP signaling pathways

Zhu, Huili; Liu, Xiaoqian; Wang, Xiaoxuan; Li, Yulei; Ma, Fang; Tan, Bo; Zhou, Peilan; Fu, Fenghua; Su, Ruibin

doi:10.1016/j.ejphar.2023.176038

Cited by 3 publications

(1 citation statement)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies describe the involvement of other coupling partners including G αq 25 , 27 – 30 , although there are also studies showing that G αq KO mice inhibit only partially HTR 27 , suggesting additional contributing mechanisms in HTR. Moreover, studies have reported the involvement of G αs proteins 30 , G βγ subunits 31 , and β-arrestins 11 , 12 in HTR.…”

Section: Resultsmentioning

confidence: 99%

G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits

Kossatz,

Diez-Alarcia,

Gaitonde

et al. 2024

Nat Commun

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation. Complete (in)activation of all pathways can be counterproductive for specific therapeutic applications. This is the case for the serotonin 2 A receptor (5-HT2AR), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HT2AR coupling signature in response to different signaling probes, and its physiological consequences by combining computational modeling, in vitro and in vivo experiments with human postmortem brain studies. We show how chemical modification of the endogenous agonist serotonin dramatically impacts the G protein coupling profile of the 5-HT2AR and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by Gαq protein activation, whereas psychosis-related behavior is modulated through Gαi1 stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.

show abstract

Section: Resultsmentioning

confidence: 99%

G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits

Kossatz,

Diez-Alarcia,

Gaitonde

et al. 2024

Nat Commun

View full text Add to dashboard Cite

show abstract

Comparative transcriptomic characterization of the ovary in the spawning process of the mud crab Scylla paramamosain

Tu,

Yu,

et al. 2024

Dev Growth Differ

View full text Add to dashboard Cite

Oviposition is induced upon mating in most insects. Spawning is a physiological process that is fundamental for the reproduction of Scylla paramamosain. However, the molecular mechanisms underlying the spawning process in this species are poorly understood. Herein, comprehensive ovary transcriptomic analysis was conducted at the germinal vesicle breakdown stage (GVBD), spawning stage, 0.5 h post‐spawning stage, and 24 h post‐spawning stage of S. paramamosain for gene discovery. A total of 67,230 unigenes were generated, and 27,975 (41.61%) unigenes were annotated. Meanwhile, the differentially expressed genes (DEGs) between the different groups were identified, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was subsequently conducted. These results suggested that octopamine (OA) and tyramine (TA) could induce oviposition, while dopamine (DA) and serotonin (5‐hydroxytryptamine [5‐HT]) inhibit oviposition. The 20‐hydroxyecdysone (20E) and methyl farnesoate (MF) signal pathways might be positively associated with oviposition. Furthermore, numerous transcripts that encode neuropeptides and their G‐protein‐coupled receptors (GPCRs), such as CNMamide, RYamide, ecdysis‐triggering hormone (ETH), GPA2/GPB5 receptor, and Moody receptor, appear to be differentially expressed during the spawning process. Eleven unigenes were selected for qRT‐PCR and the pattern was found to be consistent with the transcriptome expression pattern. Our work is the first spawning‐related investigation of S. paramamosain focusing on the ovary at the whole transcriptome level. These findings assist in improving our understanding of spawning regulation in S. paramamosain and provide information for oviposition studies in other crustaceans.

show abstract

The Discovery of Novel α2a Adrenergic Receptor Agonists Only Coupling to Gαi/O Proteins by Virtual Screening

Zhou,

Lu,

Zhu

et al. 2024

IJMS

View full text Add to dashboard Cite

Most α2-AR agonists derived from dexmedetomidine have few structural differences between them and have no selectivity for α2A/2B-AR or Gi/Gs, which can lead to side effects in drugs. To obtain novel and potent α2A-AR agonists, we performed virtual screening for human α2A-AR and α2B-AR to find α2A-AR agonists with higher selectivity. Compound P300–2342 and its three analogs significantly decreased the locomotor activity of mice (p < 0.05). Furthermore, P300–2342 and its three analogs inhibited the binding of [3H] Rauwolscine with IC50 values of 7.72 ± 0.76 and 12.23 ± 0.11 μM, respectively, to α2A-AR and α2B-AR. In α2A-AR-HEK293 cells, P300–2342 decreased forskolin-stimulated cAMP production without increasing cAMP production, which indicated that P300–2342 activated α2A-AR with coupling to the Gαi/o pathway but without Gαs coupling. P300–2342 exhibited no agonist but slight antagonist activities in α2B-AR. Similar results were obtained for the analogs of P300–2342. The docking results showed that P300–2342 formed π-hydrogen bonds with Y394, V114 in α2A-AR, and V93 in α2B-AR. Three analogs of P300–2342 formed several π-hydrogen bonds with V114, Y196, F390 in α2A-AR, and V93 in α2B-AR. We believe that these molecules can serve as leads for the further optimization of α2A-AR agonists with potentially few side effects.

show abstract

Gβγ subunit inhibitor decreases DOM-induced head twitch response via the PLCβ/IP3/Ca2+/ERK and cAMP signaling pathways

Cited by 3 publications

References 84 publications

G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits

G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits

Comparative transcriptomic characterization of the ovary in the spawning process of the mud crab Scylla paramamosain

The Discovery of Novel α2a Adrenergic Receptor Agonists Only Coupling to Gαi/O Proteins by Virtual Screening

Contact Info

Product

Resources

About