Fig. 3.

Illustration of the cellular mechanisms by which BK channels mediate β-adrenergic relaxation in UBSM cells with demonstration of the differential outcomes in the wild-type (WT) mouse (top) and the BK-knockout (KO) mouse (bottom), respectively. In UBSM cells from WT mice, functionally active BK channels regulate Ca²⁺ entry via L-type voltage-dependent Ca²⁺ channels (VDCC), and, thus, contractility (top). In addition, BK channels are under the local control of the so-called “Ca²⁺ sparks” caused by Ca²⁺ release from the ryanodine receptors of the sarcoplasmic reticulum, adjacent to the cell membrane. Following permanent BK channel pore forming α-subunit gene deletion in the BK channel KO mouse, an adaptive compensatory upregulation of the β-AR/cAMP/PKA signaling pathway develops. The enhanced β-AR/PKA activity compensates for the increased Ca²⁺ entry via L-type VDCC that occurs due to sustained membrane depolarization in the absence of the BK channels. AC, adenylyl cyclase; BK, large-conductance voltage- and Ca²⁺-activated K⁺ channels; β-AR, β-adrenergic receptors; VDCC, L-type voltage-dependent Ca²⁺ channels; G_s, stimulatory G protein; PKA, protein kinase-A; PLB, phospholamban; PLC, phospholipase C; RyR, ryanodine receptor; SR, sarcoplasmic reticulum. This figure is based on information from Brown et al. (21).