Functional reconstitution of a chloride channel bares its soul

Abstract

Chloride channels have been called the poor cousins of the aristocratic cation channels because their physiological functions involve “cleaning up the mess after the party” (1). Although Cl− channels are not as glamorous as the Na+, Ca2+, and K+ channels dominating neuronal signaling, their functions are indispensable (2), as exemplified by cholera caused by superactivation of a Cl− channel (CFTR) in the gut and cystic fibrosis caused by insufficiency of the same Cl− channel in the lung. In part, our understanding of these navels of negativity has been slow to ripen because the molecular zoo of Cl− channels is incomplete. Humans have >200 cation channel genes in >20 families, but only four Cl− channel families comprised of a paltry 34 genes were known until recently. This limited sampling has restricted efforts to uncover the essence of Cl− channel pores. Therefore, a sensation occurred when the Cl− channel gene superfamily blossomed in size in 2008 with the addition of a 10-gene family called TMEM16 , also called Anoctamin (3⇓–5). TMEM16A and TMEM16B encode subunits of Ca2+-activated Cl− channels (CaCCs) that are widely expressed throughout the body. CaCCs open when intracellular Ca2+ rises, for example following activation of G protein-coupled receptors by certain hormones. CaCCs’ best known function is in epithelial fluid secretion, a role played in parallel with CFTR (Fig. 1). The aqueous portion of secretions such as tears, saliva, milk, and pancreatic juice is produced by cells that actively accumulate Cl− from their blood-side by pumps and transporters, and then release Cl− into the glandular ducts through Cl− channels on the other side of the cell. Cl− efflux drives fluid secretion as Na+ and water follow … [↵][1]1To whom correspondence should be addressed. E-mail: criss.hartzell{at}emory.edu. [1]: #xref-corresp-1-1