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Decreased Expression of Caveolin-1 and Altered Regulation of Mitogen-Activated Protein Kinase in Cultured Bovine Parathyroid Cells and Human Parathyroid Adenomas

Endocrine-Hypertension Division and Departments of Medicine (O.K., I.K., R.R.B., E.M.B.) and Surgery (F.D.M.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; and Scantibodies Laboratories (T.C., P.G.), Santee, California 92071

Address all correspondence and requests for reprints to: Dr. Olga Kifor, Endocrine-Hypertension Division, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: okifor{at}rics.bwh.harvard.edu.

Caveolins are key components of caveolae membranes. The calcium-sensing receptor (CaR) resides within caveolin-rich membrane domains in bovine parathyroid (PT) cells. Recent studies reported reduced CaR expression, and abnormal calcium-sensing in PT tumors. To examine this altered CaR signaling, we investigated ERK activation after CaR stimulation in human and bovine PT cells. In freshly prepared bovine PT cells, high extracellular calcium (Ca²⁺₀) stimulates ERK1/2 phosphorylation, and activated ERK1/2 colocalizes with caveolin-1 at the plasma membrane but fails to translocate to the nucleus, and cell proliferation is low. In cultured bovine PT cells, CaR and caveolin-1 levels are reduced; activated ERK1/2 localizes in the cell periphery at 10 min and in the perinuclear and nuclear regions at 60 min after exposure to high Ca²⁺₀, and cell proliferation is increased. In PT cells from adenomas, there are high levels of caveolin-2, variably reduced caveolin-1, and hyperactivation of ERK1/2, which colocalizes with caveolin-1 in some cells, but localizes in the cytosol and nucleus in others. Finally, caveolin-1 negative human PT cells exhibit reduced suppressibility of PTH secretion by high Ca²⁺₀. Thus, CaR and caveolin-1 colocalize in PT cells, and reduced levels of caveolin-1 could participate in the abnormal cellular function and proliferation of cultured bovine PT cells and PT adenomas.

This work was supported by generous grants from the NIH (DK41415, 48330, and 52005), NPS Pharmaceuticals, and the St. Giles Foundation.

Abbreviations: BrdU, 5-Bromo-2'-deoxy-uridine; Ca²⁺₀, extracellular calcium; CaR, calcium-sensing receptor; Elk-1, Ets-like protein-1; HEK293, human embryonic kidney (cells); HEKCaR, CaR-transfected HEK293 cells; MBS, 2-(N-morpholino)-ethanesulfonic acid-buffered saline; pElk-1, phosphorylated Elk-1; pERK1/2, phosphorylated ERK1/2; PKC, protein kinase C; PLA₂, phospholipase A₂; PT, parathyroid; SDS, sodium dodecyl sulfate.

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