Switching of G-protein Usage by the Calcium-sensing Receptor Reverses Its Effect on Parathyroid Hormone-related Protein Secretion in Normal Versus Malignant Breast Cells

Abstract

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that signals in response to extracellular calcium and regulates parathyroid hormone secretion. The CaR is also expressed on normal mammary epithelial cells (MMECs), where it has been shown to inhibit secretion of parathyroid hormone-related protein (PTHrP) and participate in the regulation of calcium and bone metabolism during lactation. In contrast to normal breast cells, the CaR has been reported to stimulate PTHrP production by breast cancer cells. In this study, we confirmed

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

“…Notably, the effect of the calcium receptor to inhibit mammary gland production of PTHrP is reversed in certain malignant breast cancers, such that altered G protein coupling causes the calcium receptor to stimulate rather than inhibit the production of PTHrP (592). This may explain why a positive feedback loop results when certain breast cancers produce PTHrP to resorb bone, and the released calcium acts through the calcium receptor to stimulate more PTHrP rather than inhibiting it.…”

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

“…Lower levels of cAMP eventually result in decreased secretion of the PTH-related protein (PTHrP), which, among others, is involved in bone and teeth development [66]. Interestingly, Mamillapalli and colleagues have provided evidence that the alternative use of the G s subunit stimulates AC activity and, thus, cAMP production [67].…”

Physiology and pathophysiology of the calcium-sensing receptor in the kidney

“…In addition to inhibiting adenylate cyclase via G i , the CaSR can also lower cAMP indirectly by increasing intracellular Ca 2ϩ (Ca i 2ϩ ), thereby reducing the activity of Ca 2ϩ -inhibitable adenylate cyclase or activating phosphodiesterase (52). In occasional cells, the CaSR activates G s , the stimulatory G protein stimulating adenylate cyclase (99). The receptor regulates diverse other intracellular signaling systems, including mitogen-activated protein kinases (MAPKs) [e.g., extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, and c-Jun NH 2 -terminal kinase (JNK)], phospholipases A 2 and D, and the epidermal growth factor (EGF) receptor, a recently reviewed topic (72).…”