Calcium-sensing Receptor-mediated ERK1/2 Activation Requires Gαi2 Coupling and Dynamin-independent Receptor Internalization

Holstein, Deborah; Berg, Kelly A.; Leeb-Lundberg, L.M. Fredrik; Olson, Merle S.; Saunders, Christine

doi:10.1074/jbc.m312039200

Cited by 48 publications

(36 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In detail, it has been reported that the activation of CASR by its agonists or the calcimimetic NPS R568, which binds to the transmembrane domains (TMDs) of the receptor and activates it through an allosteric mechanism, stimulates the proliferation of several cell types, action that likely involves CASR-mediated activation of MAPK, as observed in rat fibroblasts and ovarian surface cells (McNeil et al 1998b; review by and Hobson et al (2003)). Indeed, in bovine parathyroid and in CASR-transfected HEK cells, elevating Ca 2C or adding NPS R-467 elicited rapid, dosedependent phosphorylation of MAPK3 and 1 (Kifor et al 2001, Holstein et al 2004. Our data showed Functional role of CASR in mammalian oocytes that incubation with NPS R-467 resulted in an increase in MAPK 3/1 activity at 15 min which still remained high at 26 h culture time compared with controls.…”

Section: Discussionsupporting

confidence: 47%

The extracellular calcium-sensing receptor is expressed in the cumulus–oocyte complex in mammals and modulates oocyte meiotic maturation

Santis¹,

Casavola²,

Reshkin³

et al. 2009

Reproduction

View full text Add to dashboard Cite

The extracellular calcium-sensing receptor (CASR) plays an important role in cells involved in calcium (Ca 2C ) homeostasis by directly sensing changes in the extracellular Ca 2C ion concentration. We previously reported the localization and quantitative expression of CASR protein in human oocytes. In this study, we examined the expression and the functional role of CASR during oocyte meiotic maturation in a large mammal animal model, the horse. As in humans, CASR protein was found to be expressed in equine oocytes and cumulus cells. Western-blot analysis revealed a single 130 kDa band in denuded oocytes and a doublet of 130-120 kDa in cumulus cells. CASR labeling was observed by confocal microscopy in cumulus cells and in oocytes on the plasma membrane and within the cytoplasm at all examined stages of meiosis. Functionally, the CASR allosteric effector NPS R-467, in the presence of 2.92 mM external Ca 2C , increased oocyte maturation rate in a dose-dependent manner and its stimulatory effect was attenuated by pre-treatment with the CASR antagonist NPS 2390. NPS R-467 had no effect in suboptimal external Ca 2C (0.5 mM), indicating that it requires higher external Ca 2C to promote oocyte maturation. In oocytes treated with NPS R-467, CASR staining increased at the plasmalemma and was reduced in the cytosol. Moreover, NPS R-467 increased the activity of MAPK, also called ERK, in cumulus cells and oocytes. These results provide evidence of a novel signal transduction pathway modulating oocyte meiotic maturation in mammals in addition to the well-known systemic hormones.

show abstract

Section: Discussionsupporting

confidence: 47%

The extracellular calcium-sensing receptor is expressed in the cumulus–oocyte complex in mammals and modulates oocyte meiotic maturation

Santis¹,

Casavola²,

Reshkin³

et al. 2009

Reproduction

View full text Add to dashboard Cite

show abstract

“…The efficient activation of the 990G CASR in terms of p44/42 ERK phosphorylation has been observed even at lower R-568 concentrations. The binding site for R-568 has been identified within the transmembrane domain of human CASR (Holstein et al 2004). R-568 has been demonstrated to stabilize WT and mutant CASR favoring the active receptor conformations (Miedlich et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Calcimimetic R-568 effects on activity of R990G polymorphism of calcium-sensing receptor

Terranegra¹,

Ferraretto²,

Dogliotti³

et al. 2010

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Previous studies have demonstrated a gain-of-function of the calcium-sensing receptor (CASR) gene R990G polymorphism. In this study, activation of the R990G CASR stably transfected in HEK-293 (HEK-990G) cells compared with that of the common variant (HEK-wild-type (WT)) by increasing concentrations of CaCl 2 or calcimimetic R-568 caused significantly higher intracellular free calcium concentration ([Ca 2C ] i ) and lower Ca-EC 50 . Moreover, the [Ca 2C ] i oscillation percentage was higher with a larger sinusoidal pattern in HEK-990G. R-568 induced a shift of the oscillatory events from 4 to 2 mmol/l extracellular calcium concentration in HEK-990G cells and increased the sinusoidal oscillation percentage in comparison with HEK-WT. Preincubation with thapsigargin or phospholipase C inhibitors completely prevented oscillations in both cell lines, consistent with the involvement of the inositol trisphosphate pathway, while protein kinase C inhibitor prevented oscillations in HEK-WT cells only. Finally, CaCl 2 and R-568 caused a significant increase in p44/42 extracellular signaling-regulated kinase phosphorylation, with the mean Ca-EC 50 values being significantly lower in HEK-990G. Our findings demonstrated that the 990G allele is associated with high sensitivity to R-568, which provided new evidence for differences in CASR signaling.

show abstract

“…26,27 Mitogen-activated protein kinase (MAPK) activity plays an important role in heart hypertrophy. 28 Holstein 29 showed that activation of the CaSR activates ERK-1/2 kinases. The ERK-1/2 signaling was shown to promote adaptive hypertrophy with normalized wall stress and compensation for increased load.…”

Section: Discussionmentioning

confidence: 99%

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Koleganova

Piecha

Ritz

et al. 2009

Laboratory Investigation

View full text Add to dashboard Cite

In patients with chronic renal failure, the heart undergoes remodeling, characterized by hypertrophy, fibrosis, and capillary/myocyte mismatch. In this study, we observed the effects of the calcimimetic agent R-568 on microvascular disease and interstitial fibrosis of the heart. Three-month-old male Sprague-Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and subsequently received vehicle or R-568 under two experimental protocols, one for 1 month and the other for 3 months. Echocardiography, capillary length density, volume density of interstitial tissue, and immunohistochemistry and western blots (calcium-sensing receptor, collagen I and III, transforming growth factor (TGF)-b, mitogen-activated protein kinases, and nitrotyrosine) were assessed. After SNX, weight and wall thickness of the left and the right ventricle were elevated. The ratio of heart to body weight and interventricular septum thickness were not changed by R-568 treatment. The left ventricle fractional shortening (by echocardiography) was lower in SNX; this was ameliorated by R-568. Reduced capillary length density and increased interstitial fibrosis in SNX were improved by R-568, which also reduced the expression of TGF-b, and collagen I and III. The calcimimetic increased the activation of ERK-1/2, normalized p38 and JNK signaling, and prevented oxidative stress. We conclude that lowering parathyroid hormone with a calcimimetic significantly improves cardiac histology and function but not the left ventricular mass in SNX.

show abstract

Calcium-sensing Receptor-mediated ERK1/2 Activation Requires Gαi2 Coupling and Dynamin-independent Receptor Internalization

Cited by 48 publications

References 50 publications

The extracellular calcium-sensing receptor is expressed in the cumulus–oocyte complex in mammals and modulates oocyte meiotic maturation

The extracellular calcium-sensing receptor is expressed in the cumulus–oocyte complex in mammals and modulates oocyte meiotic maturation

Calcimimetic R-568 effects on activity of R990G polymorphism of calcium-sensing receptor

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Contact Info

Product

Resources

About