We previously reported that SAK(CA), a stretch-activated, large-conductance, calcium- and voltage-activated potassium (BKCa) channel is present in chick embryonic heart. Here, we cloned SAK(CA) and identified that Stress-Axis Regulated Exon (STREX) is responsible for the stretch sensitivity. Single patch-clamp recordings from CHO cells transfected with the cloned SAKCA showed stretch sensitivity, whereas deletion of the STREX insert diminished the stretch sensitivity of the channel. Sequence analysis revealed that the ERA(672-674) sequence of the STREX is indispensable for channel stretch sensitivity and single amino acid substitution from Ala674 to Thr674 completely eliminated the stretch sensitivity. Co-expression of chick STREX-EGFP and SAK(CA) in CHO cells, induced a strong GFP signal in the cell membrane and inhibited the stretch sensitivity significantly. These results suggest that SAK(CA) senses membrane tension through an interaction between STREX and submembranous components. (C) 2009 Elsevier Inc. All rights reserved.