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Phospholipase D- and Protein Kinase C Isoenzyme-Dependent Signal Transduction Pathways Activated by the Calcitonin Receptor¹

Department of Histology and Medical Embryology (F.N., M.P., S.M.), University "La Sapienza," and Istituto Dermopatico dell’Immacolata (M.P., S.M.), Rome, Italy; Beth Israel Deaconess Medical Center (D.L.G., S.R.G.), New England Baptist Bone and Joint Institute, Harvard Medical School, Boston, Massachusetts; Department of Rheumatology (P.O.), INSERM, Unit 349, Lariboisiere Hospital, Paris, France; Department of Experimental Medicine (A.T.), University of L’Aquila, Italy

Address all correspondence and requests for reprints to: Anna Teti, Ph.D., Department of Experimental Medicine, via Vetoio, Coppito 2, 67100 L’Aquila, Italy. E-mail: teti{at}univaq.it

The calcitonin receptor expressed by the porcine LLC-PK₁ renal tubule cells is a seven-transmembrane domain, G protein-coupled receptor activating adenylyl-cyclase and phospholipase C. Salmon calcitonin stimulated dose- and time-dependent release of the phospholipase D-dependent phosphatidylcholine product [³H]choline with an EC₅₀ = 2.5 ± 0.3 x 10^-8 M, similar to that determined for phosphoinositide metabolism (EC₅₀ = 4.5 ± 1.0 x 10^-8 M). The hormone failed to induce release of [³H]phosphocholine and [³H]glycerophosphocholine, ruling out activation of phosphatydilcholine-specific phospholipase C and phospholipase A. Calcitonin stimulated phosphatidic acid, a product of phospholipase D-dependent phosphatydilcholine hydrolysis. Activation of phospholipase D was confirmed by release of [³H]phosphatydilethanol, a specific and stable product in the presence of a primary alcohol. Activation of calcitonin receptor induced diacylglycerol formation, with a rapid peak followed by a prolonged increase, due to activation of phospholipase C and of phospholipase D. Consequently, the protein kinase-C, but not the isoenzyme, was cytosol-to-membrane translocated by approximately 50% after 20 min exposure to calcitonin, whereas protein kinase-C, which was approximately 40% membrane-linked in unstimulated cells, translocated by approximately 19%. The human calcitonin receptor expressed by BIN-67 ovary tumor cells, although displaying higher affinity for calcitonin, failed to activate phospholipase D and protein kinase-C in response to the hormone. This receptor lacks the G protein binding consensus site due to the presence of a 48-bp cassette encoding for a 16-amino acid insert in the predicted first intracellular loop. This modification is likely to prevent the calcitonin receptor from associating to phospholipase-coupled signaling.

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