ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells

Hong

et al. 2020

IJMS

Zinc is a trace metal ion in the central nervous system that plays important biological roles, such as in catalysis, structure, and regulation. It contributes to antioxidant function and the proper functioning of the immune system. In view of these characteristics of zinc, it plays an important role in neurophysiology, which leads to cell growth and cell proliferation. However, after brain disease, excessively released and accumulated zinc ions cause neurotoxic damage to postsynaptic neurons. On the other hand, zinc deficiency induces degeneration and cognitive decline disorders, such as increased neuronal death and decreased learning and memory. Given the importance of balance in this context, zinc is a biological component that plays an important physiological role in the central nervous system, but a pathophysiological role in major neurological disorders. In this review, we focus on the multiple roles of zinc in the brain.

Section: Zinc Is Essential For Cell Growthmentioning

confidence: 99%

Zinc in the Brain: Friend or Foe?

Hong

et al. 2020

IJMS

“…GPR39 plays an important role in wound healing, depression, in ammatory bowel diseases, alcohol use disorder, insulin secretion and several cancers [23,46,[48][49][50][51][52]. However, the neuroprotective function of GPR39 has been partially con rmed.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of GPR39 and related subsequent signaling cascade has been identi ed in several cells and shown to regulate a vast array of physiological functions, such as proliferation, differentiation, ion transport and tight junction formation [16]. Moreover, activation of GPR39 has been demonstrated to promote wound healing, ameliorate symptoms of in ammatory bowel diseases, dampen epileptic seizure activity, reduce anxietylike behaviors and regulate insulin secretion and malignant progression of several cancers [17][18][19][20][21][22][23][24]. Recently, accumulating in vitro evidence demonstrated that GPR39 exhibits anti-in ammatory activity by reducing the expression of pro-in ammatory cytokines(IL-1β IL-6), enhancing anti-in ammatory cytokines production (IL-10), ameliorating oxidative stress and mitochondrial dysfunction [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Activation of GPR39 With TC-G 1008 Attenuates Neuroinflammation Via SIRT1/PGC-1α/Nrf2 Pathway Post Neonatal Hypoxic-ischemic Injury in Rats

Xie

Jiang

Doycheva

et al. 2021

Preprint

Background: Hypoxic-ischemic encephalopathy (HIE) is a severe anoxic brain injury that leads to premature mortality or long-term disabilities in infants. Neuroinflammation is a vital contributor to the pathogenic cascade post HIE and a mediator to secondary neuronal death. As a plasma membrane G-protein coupled receptor, GPR39, exhibits anti-inflammatory activity in several diseases. This study aimed to explore the neuroprotective function of GPR39 through inhibition of inflammation post hypoxic-ischemic (HI) injury and to elaborate the contribution of sirtuin 1(SIRT1)/ peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)/ nuclear factor, erythroid 2 like 2(Nrf2) in G protein-coupled receptor 39 (GPR39)-mediated protection.Methods: A total of 206 10-day old Sprague Dawley rat pups were subjected to HIE or sham surgery. TC-G 1008 was administered intranasally at 1h, 25h, 49h, and 73h post HIE induction. SIRT1 inhibitor EX527, GPR39 CRISPR, and PGC-1α CRISPR were administered to elucidate the underlying mechanisms. Brain infarct area, short-term and long-term neurobehavioral tests, Nissl staining, western blot, and immunofluorescence staining were performed post HIE.Results: The expression of GPR39 and pathway-related proteins, SIRT1、PGC-1α and Nrf2 were increased in a time-dependent manner, peaking at 24 h or 48h post HIE. Intranasal administration of TC-G 1008 reduced the percent infarcted area and improved short-term and long-term neurological deficits. Moreover, TC-G 1008 treatment significantly increased the expression of SIRT1, PGC-1α, Nrf2, IL-6, IL-1β, and TNF-α. GPR39 CRISPR EX527 and PGC-1α CRISPR abolished GPR39’s neuroprotective effects post HIE.Conclusions:TC-G 1008 attenuated neuroinflammation in part via the SIRT1/PGC-1α/Nrf2 pathway in a neonatal rat model of HIE. TC-G 1008 may be a novel therapeutic target for treatment post neonatal HIE injury.

“…Other KCC family members are essential for regulating epithelial cell volume, a function linked to morphological changes underlying formation of plasma membrane protrusions involved in metastasis as well as cell proliferation [ 166 ]. Studies in breast cancer cells show that KCC3 is upregulated by ZnR/GPR39 in the ER+ cell lines [ 167 ]. A recent study reports that ZnR/GPR39 activation in breast cancer cells leads to activation of K + /Cl - cotransporter KCC3, which may locally affect cell volume resulting in formation of protrusions [ 53 ].…”

Section: The Zinc Sensing Receptor Znr/gpr39 and Cancermentioning

confidence: 99%

Zinc Signaling in the Mammary Gland: For Better and for Worse

Chakraborty

Hershfinkel

2021

Biomedicines

Self Cite

Zinc (Zn2+) plays an essential role in epithelial physiology. Among its many effects, most prominent is its action to accelerate cell proliferation, thereby modulating wound healing. It also mediates affects in the gastrointestinal system, in the testes, and in secretory organs, including the pancreas, salivary, and prostate glands. On the cellular level, Zn2+ is involved in protein folding, DNA, and RNA synthesis, and in the function of numerous enzymes. In the mammary gland, Zn2+ accumulation in maternal milk is essential for supporting infant growth during the neonatal period. Importantly, Zn2+ signaling also has direct roles in controlling mammary gland development or, alternatively, involution. During breast cancer progression, accumulation or redistribution of Zn2+ occurs in the mammary gland, with aberrant Zn2+ signaling observed in the malignant cells. Here, we review the current understanding of the role of in Zn2+ the mammary gland, and the proteins controlling cellular Zn2+ homeostasis and signaling, including Zn2+ transporters and the Gq-coupled Zn2+ sensing receptor, ZnR/GPR39. Significant advances in our understanding of Zn2+ signaling in the normal mammary gland as well as in the context of breast cancer provides new avenues for identification of specific targets for breast cancer therapy.