Effects of divalent cations and of a calcimimetic on adrenocorticotropic hormone release in pituitary tumor cells.
The calcium sensing receptor (CaSR), a member of the G-protein coupled receptor family, is expressed on a variety of cell types and responds to extracellular calcium. We have characterized pharmacological properties of (+/-)NPS 568, a calcimimetic, toward cloned rat brain extracellular Ca2+-sensing receptor (CaSR) expressed in Chinese hamster ovary (CHO) cells and constitutive mouse CaSR in AtT-20 cells. In the presence of 1.3 mM Ca2+, the calcimimetic displayed a potency in the micromolar range in augmenting the inositol phosphates (IP) response in both cell lines and behaved as a full agonist. (+/-)NPS 568 stimulated formation of arachidonic acid release in CHO(CaSR) with a similar potency. The IP dose response curves of (+/-)NPS 568 were shifted to the left in the presence of increasing Ca2+, indicating that the potency of the drug is dependent on extracellular Ca2+ in both cells. In AtT-20 cells, Ca2+ and Ba2+, two CaSR agonists, induced a potent stimulation of adrenocorticotropic hormone (ACTH) secretion. In the presence of 1.8 mM Ca2+, (+/-)NPS 568 led to a dose dependent secretion of ACTH with an EC50 of 0.3 microM and a maximal effect comparable to Ca2+. The similar potency of the calcimimetic on IP and ACTH responses and the sensitivity of these responses to extracellular Ca2+ indicate that the Ca2+-sensing receptor expressed in AtT-20 cells is implicated in ACTH release. These data further characterize the pharmacology of the Ca2+-sensing receptor and argue for a role for extracellular Ca2+ and CaSRs in controlling ACTH secretion, a hormone implicated in several types of stress.
Ferry
S
S
Laboratoire de Neurobiologie Cellulaire et Moléculaire, UPR9040 du CNRS, Gif sur Yvette, France.
Chatel
B
B
Dodd
R H
RH
Lair
C
C
Gully
D
D
Maffrand
J P
JP
Ruat
M
M
D000324:Adrenocorticotropic Hormone / Q000187:drug effects / Q000378:metabolism*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001464:Barium / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000819:agonists* / Q000494:pharmacology*; D002413:Cations, Divalent; D006224:Cricetinae; D019204:GTP-Binding Proteins / Q000502:physiology; D008274:Magnesium / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics; D010627:Phenethylamines; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism*; D011437:Propylamines; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; D002413:Cations, Divalent; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D009363:Neoplasm Proteins; D010627:Phenethylamines; D011437:Propylamines; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; C473605:extracellular calcium cation-sensing receptor, rat; D001464:Barium; D000324:Adrenocorticotropic Hormone; D019204:GTP-Binding Proteins; D008274:Magnesium; D002118:Calcium