De novo expression of Kv6.3 contributes to changes in vascular smooth muscle cell excitability in a hypertensive mice strain

Abstract

Essential hypertension involves a gradual and sustained increase in total peripheral resistance, reflecting an increased vascular tone. This change associates with a depolarization of vascular myocytes, and relies on a change in the expression profile of voltage-dependent ion channels (mainly Ca 2+ and K + channels) that promotes arterial contraction. However, changes in expression and/or modulation of voltage-dependent K + channels (Kv channels) are poorly defined, due to their large molecular diversity and their vascular bed-specific expression. Here we endeavor to characterize the molecular and functional expression of Kv channels in vascular smooth muscle cells (VSMCs) and their regulation in essential hypertension, by using VSMCs from resistance (mesenteric) or conduit (aortic) arteries obtained from a hypertensive inbred mice strain, BPH, and the corresponding normotensive strain, BPN. Real-time PCR reveals a differential distribution of Kv channel subunits in the different vascular beds as well as arterial bed-specific changes under hypertension. In mesenteric arteries, the most conspicuous change was the de novo expression of Kv6.3 (Kcng3) mRNA in hypertensive animals. The functional relevance of this change was studied by using patch-clamp techniques. VSMCs from BPH arteries were more depolarized than BPN ones, and showed significantly larger capacitance values. Moreover, Kv current density in BPH VSMCs is decreased mainly due to the diminished contribution of the Kv2 component. The kinetic and pharmacological profile of Kv2 currents suggests that the expression of Kv6.3 could contribute to the natural development of hypertension.

KV2.1 and electrically silent KV channel subunits control excitability and contractility of guinea pig detrusor smooth muscle

“…Consistent with our findings, the K V 2.1 subunit has been reported to be the major K V subunit in rat and mouse DSM (9,17,41,56). From the electrically silent subunits that we identified (K V 6.2-6.3, K V 8.2, and K V 9.1-9.3), only K V 6.3 and K V 9.3 have been reported to contribute to the ScTx1-sensitive current by forming K V 2.1/6.3 and K V 2.1/9.3 ScTx1-sensitive K V heterotetramers (14,15,40). It is also well known that the K V 9.3 subunit combines only with the K V 2.1 subunit to form a functional heterotetramer and remains electrically silent if expressed alone in artificial systems (14, 32-34, 44, 45).…”

“…Stromatoxin-1 (ScTx1), a spider venom peptide isolated from the African tarantula (Stromatopelma calceata), was recently identified as a highly selective inhibitor of the K V 2.1, K V 2.2, and K V 4.2 homotetramers as well as the K V 2.1/6.3 and K V 2.1/9.3 heterotetramers (14,15,40). Studies in neurons, cerebral arteries, urethra, and DSM have confirmed that ScTx1 is a useful pharmacological tool to study the functional role of these K V channels (1,6,9,37,40,61).…”

Kv1.3 Channels Can Modulate Cell Proliferation During Phenotypic Switch by an Ion-Flux Independent Mechanism

“…6 However, looking at the expression levels of the Kv1 subfamily members ( Figure 1A), it is noticeable that contractile VSMC have a predominant expression of Kv1.5 channels (whose functional contribution has been characterized [16][17][18] ); whereas Kv1.5 expression is almost absent in cultured VSMC, where Kv1.3 expression predominates. Data from 3 different vascular beds ( Figure 1B) show that the Kv1.5 to Kv1.3 switch on proliferation is conserved in VSMC from conduit and resistance arteries, suggesting that the ratio Kv1.3:Kv1.5 is a representative parameter of the VSMC phenotype.…”

“…The specificity and potency of diphenyl phosphine oxide-1 blocking Kv1.5 currents was determined in parallel experiments using heterologously expressed Kv1.5 channels (data not shown), and the fraction of Kv1 current in both mesenteric and femoral VSMC was previously defined by using the correolide-sensitive fraction of the outward K + current. 6,18 The fact that a proproliferative role of Kv1.3 channels was described in VSMC from several human vessels 6,7 could reflect an obligatory association of Kv1.3 channels with vascular remodeling, increasing its value as a new therapeutical target. Although there are several other ion channels (including TRPC1, 2 T-type calcium channels, 1 Kv3.4 channels, 3,4 and IK1 channels 5,25 ) whose expression and/or function has been linked to VSMC proliferation, the information regarding conservation across different vascular beds and/or species is missed for most of these candidates.…”

Kv1.3 channels modulate human vascular smooth muscle cells proliferation independently of mTOR signaling pathway

“…Ionic currents were recorded at room temperature (20-25°C) using the whole-cell configuration of the patch-clamp technique as previously described [27,30]. Membrane potential (V M ) measurements were obtained at RT using the perforated patch technique [39].…”