Downregulation of the BK Channel β1 Subunit in Genetic Hypertension

Abstract

Abstract-The molecular mechanisms underlying increased arterial tone during hypertension are unclear. In vascular smooth muscle, localized Ca 2ϩ release events through ryanodine-sensitive channels located in the sarcoplasmic reticulum (Ca 2ϩ sparks) activate large-conductance, Ca 2ϩ -sensitive K ϩ (BK) channels. Ca 2ϩ sparks and BK channels provide a negative feedback mechanism that hyperpolarizes smooth muscle and thereby opposes vasoconstriction. In this study, we examined Ca 2ϩ sparks and BK channel function in Wistar-Kyoto (WKY) rats with borderline hypertension and in spontaneously hypertensive rats (SHR), a widely used genetic model of severe hypertension. We found that the amplitude of spontaneous BK currents in WKY and SHR cells were smaller than in normotensive cells even though Ca 2ϩ sparks were of similar magnitude. BK channels in WKY and SHR cells were less sensitive to physiological changes in intracellular Ca 2ϩ than normotensive cells. Our data indicate that decreased expression of the BK channel ␤1 subunit underlies the lower Ca 2ϩ sensitivity of BK channels in SHR and WKY myocytes. We conclude that the lower expression of the ␤1 subunit during genetic borderline and severe hypertension reduced BK channel activity by decreasing the sensitivity of these channels to physiological changes in Ca 2ϩ . These results support the view that changes in the molecular composition of BK channels may be a fundamental event contributing to the development of vascular dysfunction during hypertension. Large-conductance, Ca 2ϩ -activated K ϩ (BK) channels are important regulators of vascular smooth muscle membrane potential. 4 BK channels are activated by spontaneous, local Ca 2ϩ release events (Ca 2ϩ sparks) through ryanodine-sensitive channels in the sarcoplasmic reticulum. 5 On activation by Ca 2ϩ sparks, BK channels produce large currents that hyperpolarize and relax vascular smooth muscle, which causes vasodilation. 5,6 Arterial smooth muscle BK channels are composed of pore-forming ␣ and accessory ␤1 subunits. 7,8 The ␤1 subunit, which is highly and uniquely expressed in smooth muscle, 9 enhances the sensitivity of BK channels to activation by physiological changes in Ca 2ϩ . 10,11 The functional significance of the ␤1 subunit has been demonstrated by the work of Brenner et al 9 and Plüger et al. 12 These authors found that genetically engineered mice lacking expression of the ␤1 subunit had vascular smooth muscle BK channels that were uncoupled from Ca 2ϩ sparks. These mice also had increased vascular tone and were hypertensive.Recently, we showed that a change in the molecular composition of BK channels contributes to vascular dysfunction in an angiotensin II infusion model of acquired, severe hypertension (systolic pressure Ͼ190 mm Hg). 13 We found that angiotensin II reduced the expression of the BK channel ␤1 subunit in arterial smooth muscle. The resultant BK channels had reduced Ca 2ϩ sensitivity, which significantly reduced their ability to respond to activating Ca 2ϩ sparks. Because of this, these B...

The β1-Subunit of the MaxiK Channel Associates with the Thromboxane A2 Receptor and Reduces Thromboxane A2 Functional Effects

“…In human coronary smooth muscle cells, single-channel voltage activation curves could be sorted in five groups, suggesting different degrees of MaxiK channel association with the ␤1-subunit, with ϳ70% of the channels likely in complex with 3-4 ␤1-subunits, ϳ25% of the channels in complex with 1-2 ␤1-subunits, and ϳ5% of the channels not in apparent association with the ␤1-subunit (13). Moreover, reduced expression of ␤1 is related to vascular dysfunction in hypertension (20,21), supporting a key role of this MaxiK channel subunit in vasoregulation.…”

Reduced Ca2+ Spark Activity after Subarachnoid Hemorrhage Disables BK Channel Control of Cerebral Artery Tone

“…Although altered frequency of Ca 2+ spark-induced transient BK currents has been reported in other cardiovascular diseases such as hypertension and hypovolemic shock, these phenomena have been attributed to altered BK channel function/expression. Enhanced constriction associated with hypertension and diabetes has been linked to decreased expression of the BK channel b 1 -subunit (Amberg and Santana, 2003;Brenner et al, 2000;Dong et al, 2008), whereas an acute upregulation of BK channel b 1 -subunit contributes to vasodilation and the decrease in peripheral resistance associated with hemorrhagic shock (Zhao et al, 2007). In the above-mentioned pathologies, Ca 2+ spark activity was unaltered.…”

“…Loss-of-and gain-of-function polymorphisms of KCNMA1 and KCNMB1 have been linked to asthma and blood pressure regulation in humans (Kelley-Hedgepeth et al, 2009;Tomas et al, 2008). Furthermore, decreased KCNMB1 expression causes reduced BK channel Ca 2+ and voltage sensitivity, and is linked to enhanced vasoconstriction, hypertension, and diabetes (Amberg and Santana, 2003;Brenner et al, 2000;Dong et al, 2008). These vascular pathologies have all been associated with a decrease in BK channel activity in response to Ca 2+ sparks, rather than with a reduction in Ca 2+ spark activity.…”

Constitutively active L-type Ca 2+ channels

“…Myocytes were prepared from freshly dissected rat cerebral arteries as described (13). Ca 2ϩ currents were recorded by using the whole-cell or cell-attached configuration of the patch-clamp technique with an Axopatch 200B amplifier and analyzed using PCLAMP 9.0 (Axon Instruments, Union City, CA).…”