Abstract
Calcium-sensing receptor (CaSR) has been demonstrated to be present in several tissues and cells unrelated to systemic calcium homeostasis, where it regulates a series of diverse cellular functions. A previous study indicated that CaSR is expressed in mouse glomerular mesangial cells (MCs), and stimulation of CaSR induces cell proliferation. However, the signaling cascades initiated by CaSR activation in MCs are currently unknown. In this study, our data demonstrate that CaSR mRNA and protein are expressed in a human mesangial cell line. Activating CaSR with high extracellular Ca2+ concentration ([Ca2+]o) or spermine induces a phospholipase C (PLC)-dependent increase in intracellular Ca2+ concentration ([Ca2+]i). Interestingly, the CaSR activation-induced increase in [Ca2+]i results not only from intracellular Ca2+ release from internal stores but also from canonical transient receptor potential (TRPC)-dependent Ca2+ influx. This increase in Ca2+ was attenuated by treatment with a nonselective TRPC channel blocker but not by treatment with a voltage-gated calcium blocker or Na+/Ca2+ exchanger inhibitor. Furthermore, stimulation of CaSR by high [Ca2+]o enhanced the expression of TRPC3 and TRPC6 but not TRPC1 and TRPC4, and siRNA targeting TRPC3 and TRPC6 attenuated the CaSR activation-induced [Ca2+]i increase. Further experiments indicate that 1-oleoyl-2-acetyl-sn-glycerol (OAG), a known activator of receptor-operated calcium channels, significantly enhances the CaSR activation-induced [Ca2+]i increase. Moreover, under conditions in which intracellular stores were already depleted with thapsigargin (TG), CaSR agonists also induced an increase in [Ca2+]i, suggesting that calcium influx stimulated by CaSR agonists does not require the release of calcium stores. Finally, our data indicate that pharmacological inhibition and knock down of TRPC3 and TRPC6 attenuates the CaSR activation-induced cell proliferation in human MCs. With these data, we conclude that CaSR activation mediates Ca2+ influx and cell proliferation via TRPC3 and TRPC6 in human MCs.
Highlights
Calcium-sensing receptor (CaSR), a cell-surface protein, is highly expressed in tissues and cells involved in systemic calcium homeostasis, including the parathyroid gland, kidney, and bone, where it contributes to the maintenance of systemic calcium within a narrow physiological window [1]
TPRC6 Because CaSR activation has been shown to induce TPRC1 overexpression in MCF-7 cells [2] and TRPC3 overexpression in salivary gland cells [10], we examined the effects of CaSR activation induced by high [Ca2+]o on the expression of TRPC mRNA and protein, including TRPC1, TRPC3, TRPC4 and TRPC6, which have been identified in human mesangial cells (MCs) [16]
CaSR has been demonstrated to be present in several tissues and cells unrelated to systemic calcium homeostasis, where it regulates a series of diverse cellular functions [1]
Summary
Calcium-sensing receptor (CaSR), a cell-surface protein, is highly expressed in tissues and cells involved in systemic calcium homeostasis, including the parathyroid gland, kidney, and bone, where it contributes to the maintenance of systemic calcium within a narrow physiological window [1]. CaSR is expressed in many other tissues and cells that are not primarily involved in extracellular calcium homeostasis, such as in the brain, skin, lungs, suggesting that this receptor plays additional physiological roles in the regulation of cell functions, such as cellular proliferation [2], differentiation [3] and apoptosis [4]. A previous study showed that CaSR was expressed in mouse glomerular mesangial cells (MCs), and stimulation of CaSR induced cell proliferation [8]. Nothing is currently known about the signaling cascades initiated by CaSR activation in MCs
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