SK3 channel function in the myometrium

Alterations in ion channel expression and regulation are critical to maintaining uterine quiescence during early gestation, and also lead to increases in uterine excitability at the time of labor. Mice overexpressing isoform 3 of the small conductance Ca2+-sensitive and voltage-insensitive K+ channels (SK3T/T) have a unique – and particularly relevant – labor phenotype, and serve as a mouse model of SK3 dysfunction. Specifically, these mice have weakened uterine contractility and are unable to generate substantial intrauterine pressures, and thus parturition is defective or delayed. This unique labor phenotype led us to believe that premature downregulation of SK3 activity can lead to an excitable, overly contractile uterus. We identified an association between single nucleotide polymorphisms (SNPs) in the KCNN3 gene (encodes the SK3 potassium channel protein) and preterm birth (PTB).

Our analysis revealed six SNPs associated with PTB and maternal sequencing within these regions revealed that three SNPs are associated with spontaneous PTB. These SNPs are located in a region that is highly conserved among mammalian species. One SNP of interest lies in a region that encompasses a unique promoter of an alternate exon 1C, which encodes one of the alternative forms of the channel protein. This isoform is thought to suppress the native (1A) form of the SK3 channel by reducing SK3 channel activity at the cell surface. Given that downregulation of the native channel in the myometrium is important for labor, a premature reduction is expected to lead to preterm uterine excitability and contractions. The discovery of mutations in this alternate (inhibitory) isoform of the channel is consistent with our hypothesis that defects in KCNN3 are a cause of prematurity. The goal of our laboratory is to establish whether PTB-associated KCNN3 polymorphisms increase promoter activity, causing an increase in the expression of alternate SK3 channel isoforms and to determine whether PTB-associated KCNN3 polymorphisms cause misregulated splicing of the SK3 transcript.