The Drosophila tweety family: molecular candidates for large‐conductance Ca 2+ ‐activated Cl − channels

Calcium‐activated chloride currents ( I Cl(Ca) ) can be recorded in almost all cells, but the molecular identity of the channels underlying this Cl − conductance is still incompletely understood. Here, I report that tweety , a gene located in Drosophila flightless , possesses five or six transmembrane segments, and that a human homologue of tweety (hTTYH3) is a novel large‐conductance Ca 2+ ‐activated Cl − channel, while the related gene, hTTYH1, is a swelling‐activated Cl − current. hTTYH3 is expressed in excitable tissues, including the heart, brain and skeletal muscle, whereas hTTYH1 is expressed mainly in the brain. Expression of hTTYH3 in CHO cells generated a unique Cl − current activated by an increase in the intracellular Ca 2+ concentration. The hTTYH3‐induced Cl − current had a linear current–voltage ( I–V ) relationship, a large single‐channel conductance (260 pS) and the anion permeability sequence I − > Br − > Cl − . Like native Ca 2+ ‐activated Cl − channels, the hTTYH3 channel showed complex gating kinetics and voltage‐dependent inactivation, and was dependent on micromolar intracellular Ca 2+ concentration. Expression in CHO cells of an hTTYH1 splice variant that lacks the C‐terminal glutamate‐rich domain of hTTYH1 (hTTYH1sv) generated a swelling‐activated Cl − current. I conclude that investigation of the tweety family will provide important information about large‐conductance Cl − channel molecules.