Effects of divalent cations and of a calcimimetic on adrenocorticotropic hormone release in pituitary tumor cells

Biochem Biophys Res Commun. 1997 Sep 29;238(3):866-73. doi: 10.1006/bbrc.1997.7401.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / drug effects
  • Adrenocorticotropic Hormone / metabolism*
  • Aniline Compounds / pharmacology*
  • Animals
  • Barium / pharmacology*
  • CHO Cells
  • Calcium / agonists*
  • Calcium / pharmacology*
  • Cations, Divalent
  • Cricetinae
  • GTP-Binding Proteins / physiology
  • Magnesium / pharmacology
  • Neoplasm Proteins / genetics
  • Phenethylamines
  • Pituitary Neoplasms / genetics
  • Pituitary Neoplasms / metabolism*
  • Propylamines
  • RNA, Messenger / analysis
  • Rats
  • Receptors, Calcium-Sensing
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology*
  • Transcription, Genetic / drug effects
  • Tumor Cells, Cultured

Substances

  • Aniline Compounds
  • Cations, Divalent
  • N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
  • Neoplasm Proteins
  • Phenethylamines
  • Propylamines
  • RNA, Messenger
  • Receptors, Calcium-Sensing
  • Receptors, Cell Surface
  • extracellular calcium cation-sensing receptor, rat
  • Barium
  • Adrenocorticotropic Hormone
  • GTP-Binding Proteins
  • Magnesium
  • Calcium