An unexpected finding in this study is that >50% of BK channels localized far away from RYRs so that they could not be the targets of RYRs (64.5 ± 6.2% of BK channels outside of RYR1 domains [n = 5 cells] and 65.2 ± 6.9% of BK channels outside of the RYR2 domains [n = 6 cells]). This suggests that in addition to Ca2+ sparks, other forms of Ca2+ signals could activate BK channels (Fig. 8 D). In fact, several Ca2+ sources have been demonstrated or proposed to activate BK channels. In portal vein and cerebral artery smooth muscle cells, Ca2+ from inositol trisphosphate receptors can activate STOCs (though it has yet to be determined whether underlying Ca2+ events are Ca2+ pufflike local Ca2+ signals; Kitamura et al., 1992; Zhao et al., 2010). In vascular smooth muscle and ASM, VDCCs could activate BK channels either as the form of STOCs or whole-cell IBK (Wang et al., 1997; Guia et al., 1999). Finally, nonselective Ca2+ channels can directly or indirectly open BK channels (Zou et al., 2002). More experiments are needed to elucidate the activation mechanism and role of BK channels outside the Ca2+ spark microdomains in smooth muscle.
