Proposed role for the β_1E65K subunit, resulting from a single point mutation in the β₁ subunit and leading to a gain-of-function of the BK channel and vasodilation. (A) The BK channels in smooth muscle are composed of α pore-forming subunits and β₁ subunits. Local Ca²⁺ release (Ca²⁺ sparks) through a cluster of ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) membrane activates nearby BK channels leading to membrane potential hyperpolarization, decreased influx of Ca²⁺ through voltage-dependent Ca²⁺ channels (VDCCs), and less contraction. β₁ subunits play a crucial role in the Ca²⁺ spark–BK channel negative feedback loop, since they increase the Ca²⁺-sensitivity of the pore-forming α subunit of the BK channel. (B) The mutant form of the β₁ subunit, the β_1E65K subunit, which reflects a single amino acid substitution, has an even higher efficacy in enhancing the Ca²⁺-sensitivity of BK channels resulting in their gain-of-function. Hence, the mutant β_1E65K subunit enhances the role of the Ca²⁺ spark–BK channel negative feedback mechanism in limiting vasoconstriction and effectively provides protection against diastolic hypertension.