Important roles of the Ca2+-sensing receptor in vascular health and disease

Guo, Yanjun; Yang, Xinquan; He, Jialin; Liu, Jingjing; Yang, Shi‐Ming; Dong, Hui

doi:10.1016/j.lfs.2018.08.016

Cited by 34 publications

(17 citation statements)

References 127 publications

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“…Vasodilators, such as NO and prostacyclin (Prostacyclin I 2 , PGI 2 ), released by vascular endothelial cells, which have opposite functions to endothelin, cause vasodilation by reducing the [Ca 2+ ]i concentration in vascular smooth muscle cells (Ali and Khalil, 2015;Vanhoutte et al, 2017). [Ca 2+ ]i in vascular smooth muscle cells is mainly derived from extracellular calcium entering through the cell membrane calcium channels and intracellular calcium released from the endoplasmic reticulum of vascular smooth muscle cells (Guo et al, 2018;Touyz et al, 2018;Manoury et al, 2020). In addition to calcium channels, there are also K + channels on the vascular smooth muscle cell membrane, which affects the vascular smooth muscle cell membrane potential to regulate the vasomotor function of the vessels (Manoury et al, 2020).…”

Section: Effect Of Metformin On Vascular Function/diseases Vascular Tmentioning

confidence: 99%

Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function

Mingying

et al. 2020

Front. Pharmacol.

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Metformin has been used in diabetes for more than 60 years and has excellent safety in the therapy of human type 2 diabetes (T2D). There is growing evidence that the beneficial health effects of metformin are beyond its ability to improve glucose metabolism. Metformin not only reduces the incidence of cardiovascular diseases (CVD) in T2D patients, but also reduces the burden of atherosclerosis (AS) in pre-diabetes patients. Vascular smooth muscle cells (VSMCs) function is an important factor in determining the characteristics of the entire arterial vessel. Its excessive proliferation contributes to the etiology of several types of CVD, including AS, restenosis, and pulmonary hypertension. Current studies show that metformin has a beneficial effect on VSMCs function. Therefore, this review provides a timely overview of the role and molecular mechanisms by which metformin acts through VSMCs to protect CVD.

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Section: Effect Of Metformin On Vascular Function/diseases Vascular Tmentioning

confidence: 99%

Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function

Mingying

et al. 2020

Front. Pharmacol.

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“…Recently, the CaSR PAM etelcalcetide received regulatory approval for clinical use as a more efficacious alternative for cinacalcet with a higher level of compliance (Block et al, 2017;Patel and Bridgeman, 2018;Xipell et al, 2019). CaSR expression in tissues unrelated to calcium homeostasis suggests that this receptor could also be a potential therapeutic target for cardiovascular diseases, infertility, and cancer (Ellinger, 2016;Tennakoon et al, 2016;Guo et al, 2018). Nevertheless, the precise contribution of the CaSR in these disease contexts remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Calcium-Sensing Receptor Internalization Isβ-Arrestin–Dependent and Modulated by Allosteric Ligands

et al. 2019

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G protein-coupled receptor (GPCR) internalization is crucial for the termination of GPCR activity, and in some cases is associated with G protein-independent signaling and endosomal receptor signaling. To date, internalization has been studied in great detail for class A GPCRs; whereas it is not well established to what extent the observations can be generalized to class C GPCRs, including the extracellular calcium-sensing receptor (CaSR). The CaSR is a prototypical class C GPCR that maintains stable blood calcium (Ca 21) levels by sensing minute changes in extracellular free Ca 21. It is thus necessary that the activity of the CaSR is tightly regulated, even while continuously being exposed to its endogenous agonist. Previous studies have used overexpression of intracellular proteins involved in GPCR trafficking, pathway inhibitors, and cell-surface expression or functional desensitization as indirect measures to investigate CaSR internalization. However, there is no general consensus on the processes involved, and the mechanism of CaSR internalization remains poorly understood. The current study provides new insights into the internalization mechanism of the CaSR. We have used a state-of-the-art time-resolved fluorescence resonance energy transfer-based internalization assay to directly measure CaSR internalization in real-time. We demonstrate that the CaSR displays both constitutive and concentration-dependent Ca 21-mediated internalization. For the first time, we conclusively show that CaSR internalization is sensitive to immediate positive and negative modulation by the CaSR-specific allosteric modulators N-(3-[2-chlorophenyl]propyl)-(R)-a-methyl-3-methoxybenzylamine (NPS R-568) and 2-chloro-6-[(2R)-2hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino] propoxy]benzonitrile (NPS 2143), respectively. In addition, we provide compelling evidence that CaSR internalization is b-arrestin-dependent while interestingly being largely independent of G q/11 and G i/o protein signaling. SIGNIFICANCE STATEMENT A novel highly efficient cell-based real-time internalization assay to show that calcium-sensing receptor (CaSR) internalization is b-arrestin-dependent and sensitive to modulation by allosteric ligands.

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“…Indeed, in condition of Arginase 1 hyperactivation, there is a reduction in the amount of l-arginine, which represents the substrate of NO synthesis. Consequently, the reduction of NO levels causes an increase in ROS [34,35] ( Figure 2).…”

Section: Controversialmentioning

confidence: 99%

“…Indeed, in condition of Arginase 1 hyperactivation, there is a reduction in the amount of L-arginine, which represents the substrate of NO synthesis. Consequently, the reduction of NO levels causes an increase in ROS [34,35] ( Figure 2). Moreover, in the production and release of NO from endothelium many agonists are involved; among them, acetylcholine, histamine, thrombin, serotonin, bradykinin, substance P, isoproterenol, and norepinephrine bind to specific receptors on the membrane of endothelial cells, resulting in a rapid release of NO [36].…”

Section: Controversialmentioning

confidence: 99%

The Role of Endothelial Dysfunction in Peripheral Blood Nerve Barrier: Molecular Mechanisms and Pathophysiological Implications

Maiuolo

Gliozzi

Musolino

et al. 2019

IJMS

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The exchange of solutes between the blood and the nerve tissue is mediated by specific and high selective barriers in order to ensure the integrity of the different compartments of the nervous system. At peripheral level, this function is maintained by the Blood Nerve Barrier (BNB) that, in the presence, of specific stressor stimuli can be damaged causing the onset of neurodegenerative processes. An essential component of BNB is represented by the endothelial cells surrounding the sub-structures of peripheral nerves and increasing evidence suggests that endothelial dysfunction can be considered a leading cause of the nerve degeneration. The purpose of this review is to highlight the main mechanisms involved in the impairment of endothelial cells in specific diseases associated with peripheral nerve damage, such as diabetic neuropathy, erectile dysfunction and inflammation of the sciatic nerve.

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Important roles of the Ca2+-sensing receptor in vascular health and disease

Cited by 34 publications

References 127 publications

Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function

Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function

Calcium-Sensing Receptor Internalization Isβ-Arrestin–Dependent and Modulated by Allosteric Ligands

The Role of Endothelial Dysfunction in Peripheral Blood Nerve Barrier: Molecular Mechanisms and Pathophysiological Implications

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