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Abstract
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.
In excitable cells, small-conductance Ca2+-activated potassium channels (SK channels) are responsible for the slow after-hyperpolarization that often follows an action potential. Three SK channel subunits have been molecularly characterized. The SK3 gene was targeted by homologous recombination for the insertion of a gene switch that permitted experimental regulation of SK3 expression while retaining normal SK3 promoter function. An absence of SK3 did not present overt phenotypic consequences. However, SK3 overexpression induced abnormal respiratory responses to hypoxia and compromised parturition. Both conditions were corrected by silencing the gene. The results implicate SK3 channels as potential therapeutic targets for disorders such as sleep apnea or sudden infant death syndrome and for regulating uterine contractions during labor.