EFFECTS OF DIVALENT-CATIONS AND OF A CALCIMIMETIC ON ADRENOCORTICOTROPIC HORMONE-RELEASE IN PITUITARY-TUMOR CELLS

The calcium sensing receptor (CaSR), a member a the G-protein coupled receptor family, is expressed on a variety of cell types and responds to extracellular calcium. We have characterized pharmacological proper ties of (+/-)NPS 568, a calcimimetic, toward cloned rat brain extracel lular Ca2+-sensing receptor (CaSR) expressed in Chinese hamster ovary (CHO) cells and constitutive mouse CaSR in AtT-20 cells. In the presen ce of 1.3 mM Ca2+, the calcimimetic displayed a potency in the micromo lar range in augmenting the inositol phosphates (IP) response in both cell lines and behaved as a full agonist. (+/-)NPS 568 stimulated form ation 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 cell s, Ca2+ and Ba2+, two CaSR agonists, induced a potent stimulation of a drenocorticotropia 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 mu M and a maximal effect comparable to Ca2+. The similar potency of the calcimimetic on IP and ACTH responses and the sensitivi ty of these responses to extracellular Ca2+ indicate that, the Ca2+-se nsing receptor expressed in AtT-20 cells is implicated in ACTH release . These data further characterize the pharmacology of the Ca2+-sensing receptor and argue far a role for extracellular Ca2+ and CaSRs in con trolling ACTN secretion, a hormone implicated in several types of stre ss. (C) 1997 Academic Press.