BKca Channel Alpha Subunit Variants are Differentially Modulated by the Beta-1 Subunit

Uterine myometrial cells are maintained in a quiescent state during pregnancy, in part due to hyperpolarization of the membrane by the large-conductance Ca2+-activated K+ (BKCa) channel. During labor, uterine contractility is increased and BKCa current is suppressed, however, expression of BKCa is increased, suggesting that multiple mechanisms regulate BKCa channel function. We have focused on the roles of an auxiliary β1-subunit and two N-terminal α-subunit BKCa variants, whose peptide sequences start at different methionines, MANG and MDAL. We found that whereas MDAL expression was equivalent in all samples, MANG was expressed at a higher level in myometrium from term laboring women than from term non-laboring or non-pregnant women. To examine the possibility that differential expression of these variants reduces BKCa channel activity at the onset of labor, we expressed the MANG and MDAL variants, with or without the β1-subunit, in a heterologous system and recorded currents using patch-clamp. Although whole-cell voltage-gated currents were similar between variants, the β1-subunit enhanced Ca2+ activation of MDAL but not MANG. Inside-out single-channel recordings confirmed that MANG currents were not modulated by β1. Our finding that β1 co-immunoprecipitated with both MDAL and MANG variants suggests that the longer N-terminus of MANG does not affect the interaction between BKCa α- and β1-subunits, but instead inhibits the functional modulation of the channel by β1. These observations suggest that BKCa variants are differentially regulated by auxiliary subunits to regulate myometrial contractility during pregnancy and labor.