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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.
Acute coronary syndrome in patients with cancer
Published in Expert Review of Cardiovascular Therapy, 2022
Fisayomi Shobayo, Muhammad Bajwa, Efstratios Koutroumpakis, Saamir A. Hassan, Nicolas L. Palaskas, Cezar Iliescu, Jun-Ichi Abe, Elie Mouhayar, Kaveh Karimzad, Kara A. Thompson, Anita Deswal, Syed Wamique Yusuf
Hypertension is a traditional risk factor for ACS and accelerated atherosclerosis [32]. Hypertension is also prevalent among patients with certain types of cancer, including breast and renal cancer [23,33–36]. The molecular link between hypertension and cancer is difficult to establish as both conditions share similar risk factors such as obesity and diabetes mellitus [36]. However, there is growing evidence about specific pathophysiological links. For example, in breast cancer, the activation of G-protein coupled receptor kinase 4 (GRK4) has been linked with breast cancer and hypertension [37].
Genetic variants of GRK4 influence circadian rhythm of blood pressure and response to candesartan in hypertensive patients
Published in Clinical and Experimental Hypertension, 2021
Nian Cao, Hui Tang, Miao Tian, Xue Gong, Zaicheng Xu, Binqing Zhou, Cong Lan, Caiyu Chen, Shuang Qu, Shuo Zheng, Hongmei Ren, Chao Fan, Pedro A. Jose, Chunyu Zeng, Tianyang Xia
Hypertension is a major risk factor for cardiovascular disease. By 2025, the number of hypertensive patients is expected to exceed 1.5 billion worldwide, with the number of hypertensives in China reaching 300 million (1–3). Interaction of gene and environment contribute to the development of essential hypertension. The pathogenesis of hypertension mainly includes abnormal renal water and sodium excretion, arterial dysfunction, excessive sympathetic activation, endocrine and immune disorders (4–6). Generally, it is hard to ascertain the influence of one single gene on hypertension, unless this gene interacts with others that are germane to blood pressure regulation. The G protein-coupled receptor kinase 4 (GRK4) is such a gene. Expression of GRK4 is limited to only a few organs, such as the brain, kidney and vascular system, implying its crucial role in long term control of BP and natriuresis. Actually, GRK4 plays critical roles in the activity of the peripheral dopaminergic and angiotensin system. Previous studies have shown that genetic mutants of GRK4 can lead to an increase of its activity, and further increase the function of angiotensin receptor type 1 (AT1R) in kidney, and participate further in the pathogenesis of hypertension (7–10). Antihypertensive effects of drugs, including AT1R blockers, may vary significantly among hypertensive patients with different genetic variations (11–13). Considering, that the AT1R is the target of candesartan, we speculate that GRK4 variants may play a crucial role in the different responses to candesartan in hypertensive patients. Therefore, we identified genotype of GRK4 in hypertensive patients through exon sequencing, and then analyzed the influence of GRK4 variants on the blood pressure Circadian Rhythm and antihypertensive efficiency of candesartan.
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.