platform is the chemogenetic DREADD (designer receptor exclusively activated by designer drugs) hM3Dq, which We previously demonstrated hM3Dq's ability to precisely and synthetically initiate robust [Ca2+]i transients Here, we investigate the effects that long-term CNO stimulatory culture have on hM3Dq [Ca2+]i signaling

difficult to target by small molecules because their large orthosteric peptide-binding pocket embedded deep within target, and a combination of molecular dynamics simulations and elastic network model-based methods, we Here we found a key mechanical site that modulates the collective dynamics of the receptor and used this

9 (CCR9) antagonist and previous phase III clinical candidate for the treatment of Crohn's disease, we We first synthesized a fluorescent ligand enabling equilibrium and kinetic binding studies via NanoBRET as well as fluorescence microscopy. To chemically induce CCR9 degradation, we then developed the first PROTAC targeting the IABS of GPCRs In a proof-of-principle study, we succeeded in showing that our CCR9-PROTAC is able to reduce CCR9 levels

In this review, we discuss the physiological significance of GPCR scramblase activity and the modes of Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

We hypothesized that somatic mutations in tumor samples may not be enriched within a single gene but To test this possibility, we systematically aggregated somatic cancer mutations across class A GPCRs Individual cancer types were enriched for highly impactful, recurrent mutations at selected cognate positions We also discovered that no single receptor drives this pattern, but rather multiple receptors contain enablers of a given cancer through mutations located at cognate positions across GPCR paralogs opens a window

GABAB receptors inhibit Ca2+ entry, whereas 5-HT1B receptors target SNARE complexes. We demonstrate in male and female rats that GABAB receptors receptors alter Pr, whereas 5-HT1B receptors We tested effects of changes in vesicle numbers undergoing fusion at single synapses, relative placement The effects of 5-HT1B receptor-mediated inhibition are well-fit by simulated modulation of the release Colocalization of different actions of GPCRs provide synaptic integration within presynaptic terminals

Prostaglandin (PG) signaling regulates a wide variety of physiological and pathological processes, including

Herein, we identified that ARRB1 was upregulated by HBx in vivo and in vitro.

Structural analysis of integral membrane proteins, which comprise a large proportion of druggable targets In this review, we discuss recent instructive examples of impacts from cryo-EM in therapeutics design We also discuss the opportunities afforded by emerging technological advances in cryo-EM, and the prospects

Although numerous signals are known to regulate synapses, it remains unclear which signaling mechanisms Here, we describe new tools, referred to as "SynTAMs" for synaptic targeting molecules, that enable localized We show that locally restricted suppression of postsynaptic cAMP levels or of cAMP-dependent protein-kinase activity severely impairs excitatory synapse formation without affecting neuronal maturation, dendritic Given that postsynaptic latrophilin adhesion-GPCRs drive synapse formation and produce cAMP, we suggest

Almost 20 years ago, GPCR activity was shown to be regulated by membrane potential in vitro, but whether Here we show that muscarinic GPCR mediated neuronal potentiation in vivo is voltage dependent. Depolarization alone, without a muscarinic agonist, results in a nicotinic ionotropic receptor potentiation

In this review, we discuss the relationship between structure, function, and dynamics of opioid receptors

Arrestins regulate a wide range of signaling events, most notably when bound to active G protein-coupled Among the known effectors recruited by GPCR-bound arrestins are Src family kinases, which regulate cellular Here, we focus on arrestin-3 interactions with Fgr kinase, a member of the Src family. We report that arrestin-3 modulates Fgr activity with a hallmark bell-shaped concentration-dependence We further demonstrate using NMR spectroscopy that a polyproline motif within arrestin-3 interacts directly

Here, we investigated the stringency of the two GPCRs, Mam2 and Map3, for their respective pheromones , which showed that SoMam2 (Mam2 of S. octosporus) is partially functional in S. pombe, whereas SoMap3 Next, we swapped individual domains of Mam2 and Map3 with the respective domains in SoMam2 and SoMap3 , which revealed differences between the receptors both in the intracellular regions that regulate the In particular, we demonstrated that two amino acid residues of Map3, F214 and F215, are key residues

In this study, we evaluated the role of the astrocytic Gi pathway in neuroinflammation using a Gi -coupled We found that astrocyte Gi -DREADD stimulation using clozapine N-oxide (CNO) inhibits neuroinflammation

Here, we show the conformational changes for βarr activation upon the C tail- and TM core-mediated interactions Our NMR analyses demonstrated that while the C tail-mediated interaction alone induces partial activation , in which βarr exists in equilibrium between basal and activated conformations, the TM core- and the

By stimulating human MRGPRD-expressing HeLa cells with the agonist β-alanine, we observed a release of investigated further by probing downstream signaling effectors along the Gαq/Phospholipase C (PLC) pathway, which Additionally, we investigated the constitutive (ligand-independent) and basal activity of MRGPRD and

the receptor focused on the potential therapeutic ability for growth hormone (GH) release to reduce wasting in aging individuals, as well as food intake regulation for treatment of cachexia. in the circulation does have access to a small number of CNS sites, including the arcuate nucleus, which including dopamine D1 and D2, serotonin 2C, orexin, oxytocin and melanocortin 3 receptors (MCR3), as well

Identification of a MCMV M33 mutant (M33ΔC38) for which CREB signalling was disabled, but PLCβ activation In contrast, M33ΔC38-infected DC within the vascular compartment extravasated to the salivary glands In the context of MCMV latency, spleen explants from M33ΔC38-infected mice were markedly attenuated for IMPORTANCE G protein-coupled receptors (GPCRs) act as cell surface molecular "switches" which regulate In this report, we show temporal and tissue-specific M33 signalling is required facilitating in vivo

They often form homo- and heterodimers with allosteric cross-talk between receptor entities, which contributes Here, we examined the mode of action of positive allosteric modulators (PAMs) that bind at the interface activity of these PAMs involves a key region in the central core of the GABAB2 transmembrane domain, which

effects of acute activation of Gs signaling in skeletal muscle (SKM) in vivo and its contribution to whole-body Methods: To address this question, we studied mice that express a Gs-coupled designer G protein-coupled We also identified two Gs-coupled GPCRs that are endogenously expressed by SKM at relatively high levels The acute metabolic effects of UCN2 were not mediated by SKM Gs signaling. homeostasis, most likely due to the fact that these receptors are also expressed by pancreatic islets where

However, intracellular partners linking GPCRs to TASK1 modulation are not yet well-known. We hypothesized that isoform 2 of rho-kinase (ROCK2), acting as downstream GPCRs, mediates adjustment Electrophysiological recordings were performed in hypoglossal MNs (HMNs) obtained from adult and neonatal Furthermore, ROCK activity assays were performed to evaluate the ability of various physiological GPCR knockdown both depressed AMPAergic, inspiratory-related discharge activity of adult HMNs in vivo , which

In this review, we describe the functions of multiple GPCRs expressed in HSCs, their roles in liver fibrogenesis

Here, we show that Latrophilin-1 acts in trans to mediate morphogenesis of sensory structures in the We conclude that 7TM-independent functions of Latrophilins are essential for neuronal physiology, possibly

GPCRs share a common mechanism of action via the β-arrestin scaffolding signaling complexes, which not receptor (β2AR), and metabotropic glutamate receptor 2 (mGluR2) promotes hyperphosphorylation of tau, we Here, we report that β-arrestins are not only essential for β2AR and mGluR2-mediated increase in pathogenic Increased β-arrestin1 in turn drives the accumulation of pathogenic tau, whereas reduced ARRB1 alleviates destabilizing microtubules and impeding p62/SQSTM1 autophagy flux by interfering with p62 body formation, which

In this sense, G protein-coupled receptors (GPCRs) may be a good option to try to prolong our life while maintaining good health since they have a substantial participation in a wide variety of processes of In this way, we present the analysis of a series of GPCRs whose activity has been shown to affect the lifespan of animal and human models, and in which we put a special interest in describing the molecular We also discuss the possibility of using agonist or antagonist drugs, depending on the beneficial or

Chemical communication controls a wide range of behaviors via conserved signaling networks. In this study, we investigated the role of chemical signaling in axon regeneration in Caenorhabditis We demonstrate that the chemoreceptor genes, srg-36 and srg-37 , which encode G protein-coupled receptors However, it remains unclear what signals activate the EGL-30 pathway in axon regeneration. Here, we show that SRG-36 and SRG-37 act as upstream GPCRs that activate EGL-30.

important signaling pathways in higher eukaryotes is the phosphoinositide 3-kinase (PI3K) pathway, which Here we describe the rapid and efficient characterization of multiple PI3Kγ binding single-chain camelid We identify nanobodies that stimulated lipid kinase activity, block Ras activation, and specifically Overall, our work reveals insight into PI3Kγ regulation and identifies sites that may be exploited for