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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Both GRKs and β-arrestins have multiple functions beyond their roles in receptor desensitization. There are seven GRKs, which are subdivided into four subfamilies: (1) GRK1-like (1 and 7), (2) GRK2-like (2 and 3), (3) GRK4-like (4 and 5), and (4) GRK6. GRK1 and GRK7 are limited to the regulation of visual opsins, while GRK4 has some expression in the cerebellum, kidney and testes. GRK2, the most widely studied family member, phosphorylates non-receptor substrates and interacts with D1R- and D2R-initiated signaling cascades [41]. Both GRK2 and GRK4 have been implicated in the desensitization of renal D1R, one of the best studied peripheral DARs [42]. The renal dopaminergic system is covered in Chapter 7.
The essential role of G protein-coupled receptor (GPCR) signaling in regulating T cell immunity
Published in Immunopharmacology and Immunotoxicology, 2018
G protein-coupled receptor kinases (GRKs), which consist of a family of seven serine/threonine protein kinases, are best known for their role in phosphorylating the agonist-activated GPCRs. Phosphorylation of GPCR by GRKs is a well-established mechanism for GPCR desensitization59,60. The expression of GRK1 and GRK2 has been found significantly increased in mitogen-stimulated T cell, while the expression of GRK5 and GRK6 was not increased. Studies further suggested that GRK2 might be associated with the pathogenesis of autoimmunity. The expression of GRK2 is significantly decreased in peripheral blood mononuclear cells (PBMCs) of patients with rheumatoid arthritis and multiple sclerosis61.
Emerging protein kinase inhibitors for the treatment of multiple myeloma
Published in Expert Opinion on Emerging Drugs, 2019
Judith Lind, Felix Czernilofsky, Sonia Vallet, Klaus Podar
Current MM therapies including IMiDs, proteasome inhibitors, monoclonal antbodies, the impeding Bcl-2- and exportin-targeting agents as well as CAR T cells are directed against general vulnerabilities. Novel therapeutic strategies, inhibition of protein kinases, in particular, aim to target tumor-specific driver aberrations such as genetic abnormalities and microenvironment-driven deregulations. Unlike CML, MM lacks a disease-defining genetic aberration. Nevertheless, MM is characterized by frequently occurring chromosomal translocations as well as recurrent mutations. Together with stimuli within the deregulated BM microenvironment, these genomic aberrations activate RTK, non-RTK, receptor- S/TK and non-RS/TKs. A multitude of agents targeting these protein kinases has been evaluated preclinically; however, few have advanced into clinical trials (only two into phase III trial). So far no protein kinase inhibitor has been approved for MM therapy. Recent data demonstrate single-agent activity of the pan-PIM kinase inhibitor LGH447 and the cyclin-dependent kinase inhibitor dinaciclib as well as encouraging preliminary activity of the combination of RafB- and MEK-inhibitors. Combination strategies of approved therapeutics that target both tumor and stroma cells (i.e. IMiDs, proteasome inhibitors, and monoclonal antibodies), with individualized targeted therapies are urgently needed and currently ongoing. Moreover, kinome expression profiling is likely to identify potential therapeutic targets in MM. For example, one target may be the lymphoid-restricted G protein-coupled receptor kinase 6 (GRK6) [172]. Other targets may include PBK, SRPK1, CDC7-DBF4, MELK, CHK1, PLK4, and MPS1/TTK [173,174]. These studies aim to define rationally informed treatment combinations and algorithms in order to overcome resistance and cytotoxicity and to specify predictive markers in order to identify responders. In summary, protein kinase inhibitors hold the promise of once again improving MM patient outcome.
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.