KV channels and the regulation of vascular smooth muscle tone

Abstract

VSMCs in resistance arteries and arterioles express a diverse array of K_V channels with members of the K_V 1, K_V 2 and K_V 7 families being particularly important. Members of the K_V channel family: (i) are highly expressed in VSMCs; (ii) are active at the resting membrane potential of VSMCs in vivo (-45 to -30 mV); (iii) contribute to the negative feedback regulation of VSMC membrane potential and myogenic tone; (iv) are activated by cAMP-related vasodilators, hydrogen sulfide and hydrogen peroxide; (v) are inhibited by increases in intracellular Ca²⁺ and vasoconstrictors that signal through G_q -coupled receptors; (vi) are involved in the proliferative phenotype of VSMCs; and (vii) are modulated by diseases such as hypertension, obesity, the metabolic syndrome and diabetes. Thus, K_V channels participate in every aspect of the regulation of VSMC function in both health and disease.

Keywords: KV channels; arterioles; blood flow; microcirculation; potassium channels; resistance arteries; vascular smooth muscle; vasoconstriction; vasodilation.

Figure 1

K_V channels and the regulation of arteriolar tone. Left side of the diagram shows several factors that activate K_V channels in VSMCs (see text for more information and references) leading to K⁺ -efflux through these channels, membrane hyperpolarization and ultimately, vasodilation. Right side of diagram shows factors that inhibit K_V channel activity (see text for details and references), leading to membrane depolarization and vasoconstriction.

Figure 2

The pore-forming α-subunit of K_V channels. Schematic diagram of the 6 membrane spanning domains of a typical K_V channel. The length and composition of the amino (NH₂) and the carboxy (COOH) termini vary among the large number of K_V channel isoforms expressed in VSMCs. For K_V1.5, the NH₂-terminus in the full-length version of the channel is 247 amino acids (AAs) and the COOH-terminus is 89 AAs in length. In K_V1.5, the selectivity filter (AAs 480–485) follows the 9 AA, pore helix (AAs 468–479), labeled “P” in the diagram. Modulatory K_Vβ-subunits interact with residues in the NH₂-terminus of the α-subunit. Post-synaptic density (PSD)-95 interacts with PDZ domains in the COOH-terminus of K_V channels.

Figure 3

K_V channel block with 4-aminopyridine inhibits membrane K⁺ currents, depolarizes VSMCs and constricts arterioles. Panel A shows the family of outward K⁺ currents elicited by 10 mV depolarizing voltage steps from −90 mV to 0 mV recorded in hamster cremasteric arteriolar VSMCs using the perforated patch technique [90]. Panel B shows currents in the same cell after superfusion with 3 mM 4-aminopyridine (4-AP): outward currents are virtually abolished. Panel C shows summary means ± SEM for similar experiments showing the current-voltage relationship for the data shown in Panels A and B. Panel D shows the current-voltage relationship from Panel C on an expanded scale to show that 4-AP (3 mM) inhibits currents around the resting membrane potential of these cells (~-44 mV), and shifts the reversal potential for whole-cell currents (a measure of membrane potential) to more positive potentials. Panel E shows effects of 4-AP (3 mM) on membrane potential of an isolated hamster cremasteric arteriolar VSMC recorded in current-clamp experiments using the perforated-patch technique: 4-AP depolarized the cell from ~-40 mV to ~-25 mV, consistent with the data shown in Panel D. Panel F shows summary data for experiments as in Panel E demonstrating that 4-AP (3 mM) consistently depolarizes hamster cremasteric arteriolar VSMCs. Panel G shows data from pressure-myography experiments demonstrating that 4-AP consistently constricts isolated second-order cremasteric arterioles, consistent with VSMC depolarization (Panels D–F) due to block of outward K_V currents (Panels A–C). These data show 4-AP-sensitive K_V channel currents contribute to resting membrane potential and myogenic tone in arteriolar VSMCs. Data Panels A–D modified from [90], with permission. Data in Panels E–G replotted from [88], with permission.