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Familial Hyperparathyroidism
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Luigia Cinque, Alfredo Scillitani, Vito Guarnieri
Several studies in Drosophila have demonstrated that one of the downstream target genes regulated by Gcm encodes for a protein with regulator of G-protein signaling (RGS) domain that promotes the GTP hydrolysis in the heterotrimeric G-protein α subunits and the rapid attenuation of signaling pathway by GPCR [131]. This would suggest the possibility that, also in mammals, GCMB regulates expression of an RGS protein, having the role to shut down the CaSR signaling pathway, in turn facilitating GATA3-regulated expression of GCMB [124].
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Hydrolysis of GTP occurs through three main mechanisms: (1) intrinsic GTPase activity of the α-subunit, (2) specific GTPase-activating proteins, named regulators of G protein signaling (RGSs), and (3) some effectors. The α-subunits have two domains, a ras-like GTPase domain which includes the sites for guanine nucleotide binding and effector interactions, and a helical domain. The guanine nucleotide resides in a cleft between the two domains, and the helical domain is engaged in slowing down GDP release in the inactive state. Mutational analyses [8] have identified two amino acids in the α-subunit as being essential for its intrinsic GTPase activity: a glutamine residue in the N-terminus (at position 204 in Gαi1 and 227 in Gαs), and a conserved arginine (at position 201 in Gαs, and 178 in Gαi1).
Chemokine Receptor Expression and Regulatory Mechanisms
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Ricardo M. Richardson, Ralph Snyderman, Bodduluri Haribabu
A newly described family of proteins, known as regulators of G-protein signaling (RGS), reduces the strength of G-protein signaling by enhancing its GTPase activity thus making less Gβy available (82, 83). Regulation of RGS activity could, therefore, play a role in chemoattractant receptor cross-desensitization by affecting signal strength. In this regard, transient overexpression of RGS1, RGS3 and RGS4, but not RGS2, was found to inhibit chemoattractant receptor-mediated motility in a transfected lymphoid cell line (84). In our studies, expression of RGS4 in RBL-2H3 inhibited phosphoinositide hydrolysis and intracellular Ca2+ mobilization to PAFR, but not to fMLPR or CXCR1 (85). In contrast, expression of RGS 1 blocked fMLPR-, but not PAFR-mediated Ca2+ mobilization (85). These findings lend evidence to the notion that groups of receptors may be regulated separately by specific subtypes of RGS.
The essential role of G protein-coupled receptor (GPCR) signaling in regulating T cell immunity
Published in Immunopharmacology and Immunotoxicology, 2018
Regulators of G-protein signaling (RGS) proteins are a protein superfamily responsible for negatively modulating GPCR signal transduction pathways relying on the GTPase-accelerating proteins activity of their RGS-box54,55. The RGS superfamily consists of more than 30 members in mammalian cells, and many of which are also associated with T cell-mediated immunity. It has been reported that elevated level of RGS1 reduces the inhibition of T cell migration to lymphoid-homing chemokines56. Another study demonstrated that RGS3 controls T cell trafficking in an experimental model of asthma57. One recent research also indicated that RGS16 is involved in the stimulation of T cells with IL-2 and the migration TH2 cell in vivo58.
Establishing and characterizing a novel doxorubicin-resistant acute myeloid leukaemia cell line
Published in Journal of Chemotherapy, 2023
Inês Castro, Vanessa Lopes-Rodrigues, Helena Branco, M. Helena Vasconcelos, Cristina P. R. Xavier
Furthermore, the proteins exclusively present in the HL60 cells were also analysed in terms of biological processes and protein class, in order to better define the molecular mechanism of MDR developed in the established HL-60-CDR subline. The majority of the proteins found only present in the parental cells were linked with cellular metabolic processes, and in terms of class of proteins were associated with gene-specific transcription regulator and protein modifying enzyme (Supplementary Figure S5). For instance, cathepsin G, which was found by proteomic analysis to be only present in HL60 cells (Supplementary Table S3), is a protease that participates in the presentation of antigens, stimulation of specific immune responses and neutralization of toxins, also known to be broadly expressed in AML blasts and leukaemia stem cells [51, 52] Therefore, it is easy to understand that its presence was abolished when the resistant cells were selected under drug treatment. Furthermore, the stimulator of interferon response CGAMP interactor 1 (STING1), which was only found in HL60 cells in our proteomic analysis, induces inflammatory signals that enhance phagocytosis and restrain leukaemia cell expansion [53]. The absence of this protein in the resistant cells allows cell growth and may be a mechanism of resistance. Another protein present only in the parental cells is RGS14, a member of the regulator of G-protein signalling protein family, which is implicated in diverse cellular processes such as centrosome and nuclear functions [54]. Indeed, we have showed that our resistant cells have alterations in the cell cycle profile, which could be due to the lack of this protein, as it appears necessary for centrosome targeting. Further work, with RNA interference (RNAi) of these proteins, would need to be carried out to confirm these hypothesis.
GRK2 and GRK5 as therapeutic targets and their role in maladaptive and pathological cardiac hypertrophy
Published in Expert Opinion on Therapeutic Targets, 2019
The GRK family is composed of only seven members (GRK1-7) split into three subcategories based on gene structure and sequence homology: the visual or rhodopsin-kinases subfamily (GRK1 and GRK7), the βAR kinase subfamily (GRK2 and GRK3), and the GRK4 subfamily (GRK4, GRK5, GRK6) [19]. These seven GRKs are responsible for regulating over 800 GPCRs, proving that although relatively few in number they are indispensable. They all share common structural and functional hallmarks including (1) a highly conserved NH2 terminus involved in GPCR binding, (2) a regulator of G protein signaling (RGS) homology domain (RH) that includes the (3) serine/threonine kinase domain shared by all GRKs, followed by (4) a non-conserved COOH terminus. Most family members are ubiquitously expressed at varying degrees depending the on the tissue type, with a few that are tissue restricted. GRK1 and GRK7 are restricted to the retina, targeting rhodopsin and cone opsin, respectively. GRK4 is highly expressed in the testes, but is present in lower levels in the kidney, brain, and uterus. GRK2, GRK3, GRK5, and GRK6 have been reported to be expressed in the heart. Although, GRK2 and GRK5 are the predominant cardiac isoforms and therefore are of the most studied and most interest related to cardiac hypertrophy [20]. GRK2 is largely cytoplasmic, unless it is recruited to the membrane by dissociated Gβγ after GPCR activation [19]. GRK2 is unique in that it has been shown to localize to the mitochondria where it can promote apoptosis and affect bioenergetics [21–23]. Although, the mechanism of this localization is not clear. GRK5 contains a phospholipid binding domain towards the C-terminus that promotes plasma membrane targeting. GRK5, as well as other GRK4 subfamily members, contains a nuclear localization sequence (NLS) [24] and a nuclear export signal (NES) [25] located within its kinase domain, allowing GRK5 to enter the nucleus and influence gene transcription. In contrast to GRK2, GRK5 is constitutively membrane associated due to its phospholipid binding domain (residues 552–562). It does not undergo agonist-dependent recruitment to the membrane.