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Expression of Calcium-Sensing Receptor and Characterization of Intracellular Signaling in Human Pituitary Adenomas¹

Institute of Endocrine Sciences, Ospedale Maggiore, University of Milan, and Italian Auxologic Center (L.P.), IRCCS, 20122 Milan, Italy

Address all correspondence and requests for reprints to: Anna Spada, M.D., Istituto di Scienze Endocrine Ospedale Maggiore, IRCCS, Via Francesco Sforza 35, 20122 Milan, Italy. E-mail: endosci{at}imiucca.csi.unimi.it

Extracellular Ca²⁺-sensing receptor (CaSR) has been recently identified in rat and mouse pituitary and in AtT-20 cells. The aim of the study was to investigate the presence of CaSR in the human pituitary and its signaling pathway. Normal parathyroid biopsies, autoptic normal pituitaries, and seven nonfunctioning and six GH-secreting adenomas were studied. Southern blot analysis of the RT-PCR products from pituitary adenomas indicated that the PCR fragments obtained were products of specific amplification of CaSR messenger ribonucleic acid. Sequence analysis showed nucleotide identity of these products with the available human parathyroid CaSR. By immunoblotting analysis CaSR, was detected in normal and adenomatous pituitary tissues. In all tumors studied, extracellular Ca²⁺ (2.5 mmol/L) induced a significant increase in intracellular Ca²⁺, mainly due to Ca²⁺ mobilization (from 82.7 ± 11 to 148 ± 36 nmol/L; P < 0.001). Similar results were obtained with the CaSR activators gadolinium and neomycin. Moreover, CaSR activators significantly increased cAMP levels; this effect was not mimicked by other agents able to increase intracellular Ca²⁺, such as TRH. CaSR agonists did not increase resting GH secretion in any GH-secreting adenomas, but amplified the GH response to GHRH. In this study we first demonstrate CaSR expression in the human pituitary and provides evidence for an additional mechanism by which calcium might regulate pituitary cell function.

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