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Endothelin Receptor-Effector Coupling and Signaling in Cardiac Cells
Published in Malcolm J. Lewis, Ajay M. Shah, Endothelial Modulation of Cardiac Function, 2020
McDonough et al. (1993) and Leite et al. (1994), with experiments lasting up to 72 hours, have defined a refractory state that develops as functions of duration of exposure and concentration of ET. These observations, plus the finding that removal of the free ET neither reverses the response nor restores the responsiveness of refractory cells very quickly, suggest that functional reversal occurs by way of a refractory or desensitized state, ET-ETAR**, an inaccessible ligand-receptor complex that appears at a rate (k+4) that is less than or equal to k+1, k+2 and k+3 and that dissociates slowly to regenerate unliganded ETAR. G-protein-linked receptor kinases (GRKs, specifically GRK2 and GRK5) may be activated when ET-1 interacts with its receptor and may contribute to refractoriness and dissociation of the activated complex (Ament et al., 1995).
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.