An increase in tidal volume is an important feature of the ventilatory response to hypercapnia. The neural substrate for tidal volume augmentation is the frequency of action potentials per inspiratory burst. Small-conductance, calcium-activated potassium channels, which are gated by the increases in intracellular calcium during activation, contribute to the interval between action potentials by generating an afterhyperpolarization current. The generation of mice in which one member of this class of potassium channels (SK3) can be regulated by dietary doxycycline (dox) [1] has enabled its role in the ventilatory response to carbon dioxide to be examined. Experiments were carried out in awake mice at 2 weeks of age. A control period in 100% oxygen was followed by 5 min in 5% CO₂, 95% O₂. Animals targeted for repression of SK3 (SK3 T/T) on dox showed a greater increase in tidal volume than either SK3 T/T not exposed to dox or wild type. There was no difference in the increase in respiratory rate between the three groups of animals. These results show that SK3 is an important regulator of action potential frequency during CO₂ stimulation. They also suggest that medullary neurons which contribute to respiratory pattern may be characterized by SK3 channels while those responsible for rhythm may not.