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Coexpression of Calcitonin Receptor-Like Receptor and Receptor Activity-Modifying Protein 2 or 3 Mediates the Antimigratory Effect of Adrenomedullin

Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan

Address all correspondence and requests for reprints to: Masayoshi Shichiri, M.D., Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: mshichiri.cme{at}tmd.ac.jp.

Three isoforms of the receptor activity-modifying protein (RAMP) are thought to transport the calcitonin receptor-like receptor (CRLR) to the plasma membrane to function as calcitonin gene-related peptide or adrenomedullin receptors, but their role remains largely unknown. We investigated whether coexpression of RAMP and CRLR are involved in the regulation of cell migration using a monolayer-wounding protocol. Quantification of gene transcripts revealed expression of all RAMP isoforms and CRLR in cultured rat vascular smooth muscle cells (VSMCs), RAMP2 and RAMP3 in rat endothelial cells, and RAMP1 in rat fibroblasts. CRLR expression was minimal in endothelial cells and fibroblasts. Adrenomedullin potently suppressed the migration of VSMCs, whereas calcitonin gene-related peptide did not suppress migration in any cell type. The antimigratory effect of adrenomedullin on VSMCs was potentiated by transfecting CRLR cDNA. Cotransfection of RAMP2 or RAMP3 with CRLR into VSMCs resulted in a slower migratory rate, and this effect was enhanced by adrenomedullin. Migration of fibroblasts was also suppressed after cotransfection of RAMP2 or RAMP3 with CRLR. cAMP agonists had no effect on VSMC migration, and a cAMP antagonist failed to abrogate the antimigratory effect of adrenomedullin. Thus, coexpression of CRLR and RAMP2 or RAMP3 mediates the inhibitory effect of adrenomedullin on cell migration, independent of cAMP-dependent signaling pathways.

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