Several families of functionally and structurally distinct ion channels have been identified throughout the last decade, resulting in a growing complexity in our understanding of ion transport across biological membranes. Here, we introduce a novel ; family of putative chloride channel proteins with nine bovine, murine, and human homologs identified to date. The gene family has been termed CLCA family (chloride channels, calcium-activated) based on observations that heterologous expression of several family members is associated with the appearance of a novel anion channel activity that depends on the concentration of intracellular calcium. The family members identified so far are the bovine calcium-activated chloride channel (CaCC or bCLCAl), the bovine lung endothelial cell adhesion molecule-1 (LuECAM-1), the murine calcium-activated chloride channels mCLCAl, mCLCA2, and rnCLCA3 (previously termed gob-5), and four human homologs (hCLCAl, hCLCA2, hCLCA3, and hCaCC2). Each of these homologs is characterized by a unique cellular and tissue expression pattern with most consistent expression in secretory epilhelia of the digestive, respiratory, and reproductive organs. Of special interest is the observation that several of these molecules seem to combine cell-cell adhesion properties with ion channel function. Structural analyses have revealed that a four- or five-transmembrane topography is conserved throughout the family. Their functional features as well as the cellular coexpression of several CLCA homologs with the cystic fibrosis transmembrane conductance regulator (CFTR) in numerous tissues raises the question whether CLCA family members may participate in the complex ion channel disorder of cystic fibrosis. © 2000 Bentham Science Publishers Ltd.