In summary, we demonstrate that 1-EBIO activates CFTR-mediated Cl− secretion in native human colon by coordinate activation of luminal CFTR Cl− channels and basolateral Ca2+-activated KCNN4 K+ channels, and that this mode of action potentiates residual cAMP-mediated Cl− secretion in native CF rectal tissues expressing CFTR mutants that retain residual Cl− channel function. The gene discussed is KCNN4; the disease is cystic fibrosis.