Expression and function of the K⁺ channel KCNQ genes in human arteries

Abstract

BACKGROUND AND PURPOSEKCNQ-encoded voltage-gated potassium channels (Kv7) have recently been identified as important anti-constrictor elements in rodent blood vessels but the role of these channels and the effects of their modulation in human arteries remain unknown. Here, we have assessed KCNQ gene expression and function in human arteries ex vivo. EXPERIMENTAL APPROACHFifty arteries (41 from visceral adipose tissue, 9 mesenteric arteries) were obtained from subjects undergoing elective surgery. Quantitative RT-PCR experiments using primers specific for all known KCNQ genes and immunohistochemsitry were used to show Kv7 channel expression. Wire myography and single cell electrophysiology assessed the function of these channels. KEY RESULTSKCNQ4 was expressed in all arteries assessed, with variable contributions from KCNQ1, 3 and 5. KCNQ2 was not detected. Kv7 channel isoform-dependent staining was revealed in the smooth muscle layer. In functional studies, the Kv7 channel blockers, XE991 and linopirdine increased isometric tension and inhibited K + currents. In contrast, the Kv7.1-specific blocker chromanol 293B did not affect vascular tone. Two Kv7 channel activators, retigabine and acrylamide S-1, relaxed preconstricted arteries, actions reversed by XE991. Kv7 channel activators also suppressed spontaneous contractile activity in seven arteries, reversible by XE991. CONCLUSIONS AND IMPLICATIONSThis is the first study to demonstrate not only the presence of KCNQ gene products in human arteries but also their contribution to vascular tone ex vivo. LINKED ARTICLEThis article is commented on by Mani and Byron, pp. 38-41 of this issue. To view this commentary visit http://dx

G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity

“…There are five Kv7 isoforms (Kv7.1-Kv7.5) of which Kv7.1, Kv7.4, and Kv7.5 are consistently expressed within VSM, where the predominant molecular architecture is a Kv7.4/Kv7.5 heterotetramer (2,3). Activation of Kv7 channels produces relaxation of numerous arteries (4)(5)(6)(7)(8), whereas blockade of Kv7 channels results in contraction of vessels at rest (7,(9)(10)(11) or an inhibition of endogenously derived vasorelaxations (2,(11)(12)(13). In addition, molecular reduction of Kv7.4 reduces responses to various Gs-coupled vasodilators in a number of arteries (2,11).…”

Differential Protein Kinase C-dependent Modulation of Kv7.4 and Kv7.5 Subunits of Vascular Kv7 Channels

“…Kv7 voltage-activated potassium channels are expressed in many excitable cell types, including neurons, cardiac, skeletal, vascular, and visceral myocytes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) where they function to stabilize resting membrane potential and restrict cellular excitability (6,16). The five members of the Kv7 family (Kv7.1-Kv7.5) are encoded by five mammalian genes (KCNQ1-5), and the individual gene products assemble as homomeric or heteromeric tetramers to form functional channels (17).…”

“…KCNQ1, KCNQ4, and KCNQ5 genes are expressed in the murine, rat, and human vasculature (10,13,18,19), with the KCNQ4 transcripts being most abundant in mouse and rat, and an approximately equal expression of KCNQ1, KCNQ3, KCNQ4, and KCNQ5 in human arteries (13). Pharmacological screening of functional channels in vascular smooth muscle cells suggested that Kv7.4 and/or Kv7.5 are the predominant functional isoforms (10,11,13,18). This conclusion was drawn based on the expression pattern and the ability of retigabine and flupirtine, selective Kv7.2-7.5 channel activators, to enhance Kv7 currents in freshly isolated vascular myocytes and to relax constricted arteries (10,11,13,18).…”

“…Pharmacological screening of functional channels in vascular smooth muscle cells suggested that Kv7.4 and/or Kv7.5 are the predominant functional isoforms (10,11,13,18). This conclusion was drawn based on the expression pattern and the ability of retigabine and flupirtine, selective Kv7.2-7.5 channel activators, to enhance Kv7 currents in freshly isolated vascular myocytes and to relax constricted arteries (10,11,13,18).…”

Contribution of K v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

“…Voltage-gated potassium channels (K V ) have been implicated in the control of the coronary circulation and reactive hyperemia, 1,2 but little is known about the specific molecular components. Kv channels encoded by KCNQ1-5 (K V 7.1-K V 7.5) are important regulators of the smooth muscle resting membrane potential and contractility in several different rodent and human arteries, [3][4][5][6][7][8][9][10][11] which are known to be compromised in animal models of primary and secondary hypertension. 3,6 These channels, in particular K V 7.4, are also functional end points in β-adrenoceptor-mediated relaxations.…”