Calcium- and voltage-gated BK channels in vascular smooth muscle

Abstract

Ion channels in vascular smooth muscle regulate myogenic tone and vessel contractility. In particular, activation of calcium- and voltage-gated potassium channels of large conductance (BK channels) results in outward current that shifts the membrane potential toward more negative values, triggering a negative feed-back loop on depolarization-induced calcium influx and SM contraction. In this short review, we first present the molecular basis of vascular smooth muscle BK channels and the role of subunit composition and trafficking in the regulation of myogenic tone and vascular contractility. BK channel modulation by endogenous signaling molecules, and paracrine and endocrine mediators follows. Lastly, we describe the functional changes in smooth muscle BK channels that contribute to, or are triggered by, common physiological conditions and pathologies, including obesity, diabetes, and systemic hypertension.

Keywords: Calcium signaling; KCNMB1 gene; MaxiK channel; Slo1 gene; Vascular pathophysiology; Vascular smooth muscle.

Fig. 1

Lateral view of the plasmalemma with a cross-section through two BK channel-forming slo1 proteins, also known as BK α-subunits (in blue), that contribute to form a fully functional BK channel homotetramer. In vascular smooth muscles, these subunits are associated with small, two transmembrane proteins known as BK β1 subunits (in green) that modify the biophysical and pharmacological properties of the native channel. The modular nature of slo1 proteins is underscored: each subunit contains a voltage sensor domain (VSD, in blue), a central pore– gate domain (PGD, in violet), and a long C-terminal of intracellular location termed cytosolic tail domain (CTD). Each CTD contains two Regulators of Conductance for K⁺ (RCK) domains. RCK1 includes binding sites for Ca²⁺ (labeled H for high affinity divalent recognition site) and Mg²⁺ (labeled L for low affinity divalent recognition site). RCK2 includes another H site. VSD and CTD are connected to PGD by linkers and through domain-domain interface contacts.

Fig. 2

Regulation of BK channel activity and function by subunit trafficking. Slo1 proteins traffic to the plasmalemma via a Rab4A-dependent pathway, suggesting that early endosomes transport the channel to the plasmalemma. Angiotensin II (ang II) stimulates PKC-driven internalization and degradation of surface slo1 protein, thereby reducing BK current. A significant proportion of intracellular β1 in resting arterial SM is stored within Rab11A-positive recycling endosomes. NO^•, through the activation of PKG, increases Rab11A activity, leading to the rapid surface trafficking of β1. Calcium influx through voltage-dependent calcium (Ca_V) channels activates Rho kinases, which stimulates anterograde trafficking of intracellular β1 subunits. Endothelin-1 stimulates PKC-mediated phosphorylation of Rab11A at Ser177, which reduces Rab11A activity and inhibits surface trafficking of β1. An increase in surface β1 subunits activates BK channels, whereas a decrease in surface β1 inhibits BK channels, causing corresponding changes in arterial contractility. The regulation of BK channel voltage-sensitivity by LRR26, the so-called BK γ1 subunit (in violet), is also shown.

Fig. 3

In vascular myocytes, localized intracellular Ca²⁺ signals (termed Ca²⁺ sparks) activate BK channels. Ca²⁺ sparks occur following the opening of ryanodine-sensitive Ca²⁺ release (RyR) channels located on the sarcoplasmic reticulum (SR) membrane. The effective coupling of BK channels to a Ca²⁺ spark controls the amount of current generated during each BK transient. Ca²⁺ released into the cytosol during a spark does not significantly contribute to global [Ca²⁺]_ic in arterial SM cells. Rather, repetitive transient BK currents evoke partial repolarization of the plasmalemma, which reduces the activity of voltage-dependent Ca²⁺ (Ca_V) channels. Ca²⁺ influx through Ca_v channels elevates [Ca²⁺]_ic, which triggers vasoconstriction. Intracellular Ca²⁺ is sequestered into the SR by the SR Ca²⁺-ATPase, which increases SR Ca²⁺ load, a major modulator of Ca²⁺ spark frequency. The repolarization caused by Ca²⁺ spark-induced BK channel activation decreases Ca_V channel activity, thereby reducing [Ca²⁺]_ic, with consequent partial vasodilation. The activation of transient receptor potential V4 (TRPV4) channels leads to Ca²⁺ influx that stimulates Ca²⁺ sparks and transient BK currents, leading to vasodilation.