Stoking Up BK Ca Channels in Hemorrhagic Shock

Abstract

See related article, pages 493–502 Large conductance calcium-activated potassium channels (BKCa) are abundantly expressed in smooth muscle cells (SMCs) lining the blood vessel wall. They are composed of an α-subunit (Slo) and a modulatory β1-subunit, which serves to maintain the normal high voltage- and Ca2+-sensitivity of the pore-forming α-subunit (reviewed in1,2). In the vasculature, BKCa operate by limiting Ca2+ entry and arterial contraction by repolarizing SMCs and closing voltage-dependent Ca2+ channels previously opened by pressure or vasoconstrictor agents.1 BKCa can also mediate cellular hyperpolarization and vasorelaxation as a result of spontaneous transient outward currents (STOCs) activated by the localized release of micromolar concentrations of Ca2+ (Ca2+ sparks) from ryanodine receptors located in the sarcoplasmic reticulum (SR).1 Moreover, increased frequency of Ca2+ sparks may underlie activation of BKCa by endogenous vasodilators,1 though other mechanisms undoubtedly contribute.2,3 Genetic experiments also highlight BKCa as important regulators of vascular tone and blood pressure. Deletion of the α-subunit in mice results in membrane depolarization, a complete lack of STOCs, and attenuates cGMP relaxation in isolated blood vessels.4 On the other hand, deletion of β1 impairs the coupling of Ca2+ sparks to the activation of hyperpolarizing BKCa currents and enhances agonist-induced vasoconstriction without affecting nitric oxide (NO) mediated vasorelaxation.3 Knockout of both genes leads to systemic hypertension, though in BKCa β1–null mice this is more pronounced3,4 suggesting physical interactions of the β1-subunit with other proteins, possibly other ion-conducting pores.5 Moreover, depending on the hypertensive model, β1-subunit expression can either increase2,6 or decrease.7 The latter might argue that β1 acts as a compensatory mechanism to limit development of hypertension. Consistent with this, a gain-of-function mutation in the human β1-subunit gene …