TY - JOUR
T1 - Calcium-sensing receptor stimulates PTHrP release by pathways dependent on PKC, p38 MAPK, JNK, and ERK1/2 in H-500 cells
AU - Tfelt-Hansen, J.
AU - MacLeod, R. J.
AU - Chattopadhyay, N.
AU - Yano, S.
AU - Quinn, S.
AU - Ren, X.
AU - Terwilliger, E. F.
AU - Schwarz, P.
AU - Brown, E. M.
PY - 2003/8/1
Y1 - 2003/8/1
N2 - Elevated extracellular calcium ([Ca2+]o) and other agonists potentially acting via the calcium-sensing receptor (CaR) increase parathyroid hormone-related peptide (PTHrP) release from H-500 Leydig cells. Here, we provide strong evidence for the CaR's involvement by using a dominant negative CaR that attenuates high [Ca2+]o-induced PTHrP release. This effect is likely transcriptional, because high [Ca2+]o upregulates the PTHrP transcript, an effect that is abolished by actinomycin D. Regulation of PTHrP release by the CaR involves activation of PKC as well as ERK1/2, p38 MAPK, and JNK pathways. However, we show for the first time that high [Ca2+]o-induced activation of the stress-activated protein kinase SEK1 is PKC independent, because there is an additive effect of a PKC inhibitor in combination with the JNK inhibitor on [Ca2+]o-stimulated PTHrP release. Furthermore, high [Ca2+]o, in a PKC-independent fashion, induces phosphorylation of ERK1/2, SEK1, p38 MAPK, and its downstream transcription factor ATF-2. We conclude that CaR regulation of PTHrP release in H-500 cells involves activation of PKC as well as the ERK1/2, p38 MAPK, and JNK pathways.
AB - Elevated extracellular calcium ([Ca2+]o) and other agonists potentially acting via the calcium-sensing receptor (CaR) increase parathyroid hormone-related peptide (PTHrP) release from H-500 Leydig cells. Here, we provide strong evidence for the CaR's involvement by using a dominant negative CaR that attenuates high [Ca2+]o-induced PTHrP release. This effect is likely transcriptional, because high [Ca2+]o upregulates the PTHrP transcript, an effect that is abolished by actinomycin D. Regulation of PTHrP release by the CaR involves activation of PKC as well as ERK1/2, p38 MAPK, and JNK pathways. However, we show for the first time that high [Ca2+]o-induced activation of the stress-activated protein kinase SEK1 is PKC independent, because there is an additive effect of a PKC inhibitor in combination with the JNK inhibitor on [Ca2+]o-stimulated PTHrP release. Furthermore, high [Ca2+]o, in a PKC-independent fashion, induces phosphorylation of ERK1/2, SEK1, p38 MAPK, and its downstream transcription factor ATF-2. We conclude that CaR regulation of PTHrP release in H-500 cells involves activation of PKC as well as the ERK1/2, p38 MAPK, and JNK pathways.
KW - Dominant negative
KW - G protein-coupled receptor
KW - Humoral hypercalcemia of malignancy
KW - Leydig cells
KW - Osteolysis
KW - Stress-activated protein kinase activator 1
UR - http://www.scopus.com/inward/record.url?scp=0042303745&partnerID=8YFLogxK
M3 - Journal article
C2 - 12700162
AN - SCOPUS:0042303745
SN - 1522-1555
VL - 285
JO - A J P: Endocrinology and Metabolism (Online)
JF - A J P: Endocrinology and Metabolism (Online)
IS - 2 48-2
ER -