The calcium sensing receptor (CaSR) promotes Rab27B expression and activity to control secretion in breast cancer cells

Zavala-Barrera, Cesar; del-Río-Robles, Jorge Eduardo; García‐Jiménez, Irving; Egusquiza-Alvarez, Carlos Alejandro; Hernández-Maldonado, Jennifer Paulina; Vázquez‐Prado, José; Reyes‐Cruz, Guadalupe

doi:10.1016/j.bbamcr.2021.119026

Cited by 10 publications

(13 citation statements)

References 53 publications

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“…Abnormal CaSR expression and function was found associated not only with calciotropic disorders, but also with diseases with-no obvious link to the calciotropic systems [25, 75, 76]. CaSR has been observed to control numerous cellular processes such as secretion, differentiation, proliferation, apoptosis, and gene expression including its own [24, 77].…”

Section: Discussionmentioning

confidence: 99%

Low Molecular Weight Hyaluronan Inhibits Lung Epithelial Ion Channels by Activating the Calcium-Sensing Receptor

Lazrak

Song

et al. 2022

Preprint

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Herein, we tested the hypothesis low molecular weight hyaluronan (LMW-HA) inhibits lung epithelial ion transport in-vivo, ex-vivo, and in-vitro by activating the calcium-sensing receptor (CaSR). Intranasal instillation of LMW-HA (150microg/ml) to C57BL/6 mice inhibited their alveolar fluid clearance (AFC) by 75%, increased the epithelial lining fluid (ELF) thickness threefold, and lung wet/dry (W/D) ratio by 20% 24hrs later. Incubation of lung slices from mouse and human lungs with 150microg/ml LMW-HA decreased the open probability (Po) of ENaC in ATII cell by more than 50% in 4hrs, inhibited amiloride sensitive short circuit current (SCC) 4hrs post exposure, and Cl- current through CFTR by more than 70%, and Na,K-ATPase current by 66% at 24hrs. In all cases the inhibitory effect of LMW-HA on lung epithelial ion transport in vivo, ex vivo, and in vitro preparations were reversed by the administration of 1microM of NPS2143, a CaSR inhibitor, or 150microg/ml HMW-HA. In HEK-293 cells co-transfected with CaSR and the calcium sensitive Cl- channel TMEM16-A, LMW-HA activated an inward Cl- current. These data are the first demonstration of the inhibitory effects of LMW-HA on lung epithelial ion and water transport and are due to the activation of CaSR and its downstream signaling cascades.

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Section: Discussionmentioning

confidence: 99%

Low Molecular Weight Hyaluronan Inhibits Lung Epithelial Ion Channels by Activating the Calcium-Sensing Receptor

Lazrak

Song

et al. 2022

Preprint

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“…Interestingly, metastatic breast cancer cells seem to exploit CaSR capability to drive cytokine secretion, in order to promote their chemotaxis and angiogenesis, as observed in the highly invasive MDA-MB-231 breast cancer cell line stimulated with CaSR allosteric modulator NPS-R568 (Hernández-Bedolla et al, 2015;Hernández-Bedolla et al, 2016). Furthermore, in MDA-MB-231 and in the MCF-7 breast cancer cell lines, CaSR stimulation was found to enhance the expression of Rab27B, a Rab GTPase that is involved in endosomal trafficking (Zhen and Stenmark, 2015), promoting in this way the secretion of proinflammatory cytokines and chemokines such as IL-6, IL-1β, IL-8, IP-10 and RANTES (Zavala-Barrera et al, 2021).…”

Section: In Other Tissuesmentioning

confidence: 93%

The calcium-sensing receptor in inflammation: Recent updates

Iamartino

Brandi²

2022

Front. Physiol.

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The Calcium-Sensing Receptor (CaSR) is a member of the class C of G-proteins coupled receptors (GPCRs), it plays a pivotal role in calcium homeostasis by directly controlling calcium excretion in the kidneys and indirectly by regulating parathyroid hormone (PTH) release from the parathyroid glands. The CaSR is found to be ubiquitously expressed in the body, playing a plethora of additional functions spanning from fluid secretion, insulin release, neuronal development, vessel tone to cell proliferation and apoptosis, to name but a few. The present review aims to elucidate and clarify the emerging regulatory effects that the CaSR plays in inflammation in several tissues, where it mostly promotes pro-inflammatory responses, with the exception of the large intestine, where contradictory roles have been recently reported. The CaSR has been found to be expressed even in immune cells, where it stimulates immune response and chemokinesis. On the other hand, CaSR expression seems to be boosted under inflammatory stimulus, in particular, by pro-inflammatory cytokines. Because of this, the CaSR has been addressed as a key factor responsible for hypocalcemia and low levels of PTH that are commonly found in critically ill patients under sepsis or after burn injury. Moreover, the CaSR has been found to be implicated in autoimmune-hypoparathyroidism, recently found also in patients treated with immune-checkpoint inhibitors. Given the tight bound between the CaSR, calcium and vitamin D metabolism, we also speculate about their roles in the pathogenesis of severe acute respiratory syndrome coronavirus-19 (SARS-COVID-19) infection and their impact on patients’ prognosis. We will further explore the therapeutic potential of pharmacological targeting of the CaSR for the treatment and management of aberrant inflammatory responses.

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“…CaSR promotes Rab27b expression and drives Rab11a-dependent coupling of recycling endosomes to secretory vesicles. 261,270 The association of VAP proteins with Rab proteins has been observed to play a role in some virologic mechanisms. For example, a complex of VAPA, ORP3, and Rab7 was found to mediate human immunodeficiency virus 1-induced nuclear invaginations.…”

Section: Vaps: Highly Ca 2+ -Dependent Casr Interactorsmentioning

confidence: 99%

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

Tian,

Andrews,

Yan

et al. 2024

Chronic Diseases and Translational Medicine

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Calcium‐sensing receptor (CaSR), a family C G‐protein‐coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L‐Trp and L‐Phe), small peptides, anions (e.g., HCO3− and PO43−), and pH. CaSR‐mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein–protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+‐dependent cellular physiological processes and in CaSR‐dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G‐protein‐coupled receptors.

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The calcium sensing receptor (CaSR) promotes Rab27B expression and activity to control secretion in breast cancer cells

Cited by 10 publications

References 53 publications

Low Molecular Weight Hyaluronan Inhibits Lung Epithelial Ion Channels by Activating the Calcium-Sensing Receptor

Low Molecular Weight Hyaluronan Inhibits Lung Epithelial Ion Channels by Activating the Calcium-Sensing Receptor

The calcium-sensing receptor in inflammation: Recent updates

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

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