Adrenomedullin signaling pathway

Adrenomedullin (AM) is a peptide initially isolated from tumors (pheochromocytoma) of the adrenal gland. It consists of 52 amino acid residues with one intracellular disulfide bond and is a member of the calcitonin gene-related peptide (CGRP) family. It is produced by a great number of different cell types, in all tissues of the body, with the possible exception of the thyroid and thymus, and acts in many systems including the cardiovascular, renal, endocrine, reproductive, immune, nervous and musculoskeletal systems.The synthesis of AM can be influenced by physical factors such as shear stress, ventricular wall stress and hypoxia, and humoral factors such as cytokines. Inflammatory cytokines including tumor necrosis factor TNF-α, TNF-β, interleukin IL-1 and lipopolysacccharide (LPS) stimulate the synthesis and secretion of AM in endothelial cells and vascular smooth muscle cells (VSMCs) which gives this peptide a significant role in sepsis and inflammation.AM mediates its action through complexes composed of calcitonin receptor-like receptor (CL) combined with receptor activity modifying proteins (RAMP2 and RAMP3). RAMPs are single-membrane domain proteins that assist with transportation of CL to the cell surface and also interaction with G proteins.The signal transduction pathways activated by AM vary between species, organs, tissues, and cells. Biological action of AM was initially considered to be mediated solely via cAMP/PKA pathway, but subsequent studies have revealed that pleiotropic effects of AM are mediated through several additional intracellular signal transduction pathways, such as ERK/MAPK, PI3K/AKT, and NO/cGMP/PKG. The vasodilatory and hypotensive actions of AM are mediated mainly by a direct action on VSMCs to increase intracellular cAMP, and also by activation of PI3K/AKT pathway in endothelial cells to stimulate NO release. The MAKP/ERK1/2 pathway is involved in the angiogenic action of AM in endothelial cells.Many studies that show an association between AM expression and cancer. AM can stimulate cell growth and inhibit apoptosis in a variety of tumor cells, including pancreatic adenocarcinoma, prostate cancer, ovarian cancer, osteosarcoma, renal carcinoma, breast cancer, colorectal cancer and hepatocellular carcinoma. Therefore, new therapies based on blockade of the AM autocrine/paracrine system have been developed and some of them are effective in animal models.