Functional Assembly of Kv7.1/Kv7.5 Channels With Emerging Properties on Vascular Muscle Physiology

Abstract

Objective— Voltage-dependent K + (Kv) channels from the Kv7 family are expressed in blood vessels and contribute to cardiovascular physiology. Although Kv7 channel blockers trigger muscle contractions, Kv7 activators act as vasorelaxants. Kv7.1 and Kv7.5 are expressed in many vessels. Kv7.1 is under intense investigation because Kv7.1 blockers fail to modulate smooth muscle reactivity. In this study, we analyzed whether Kv7.1 and Kv7.5 may form functional heterotetrameric channels increasing the channel diversity in vascular smooth muscles. Approach and Results— Kv7.1 and Kv7.5 currents elicited in arterial myocytes, oocyte, and mammalian expression systems suggest the formation of heterotetrameric complexes. Kv7.1/Kv7.5 heteromers, exhibiting different pharmacological characteristics, participate in the arterial tone. Kv7.1/Kv7.5 associations were confirmed by coimmunoprecipitation, fluorescence resonance energy transfer, and fluorescence recovery after photobleaching experiments. Kv7.1/Kv7.5 heterotetramers were highly retained at the endoplasmic reticulum. Studies in HEK-293 cells, heart, brain, and smooth and skeletal muscles demonstrated that the predominant presence of Kv7.5 stimulates release of Kv7.1/Kv7.5 oligomers out of lipid raft microdomains. Electrophysiological studies supported that KCNE1 and KCNE3 regulatory subunits further increased the channel diversity. Finally, the analysis of rat isolated myocytes and human blood vessels demonstrated that Kv7.1 and Kv7.5 exhibited a differential expression, which may lead to channel diversity. Conclusions— Kv7.1 and Kv7.5 form heterotetrameric channels increasing the diversity of structures which fine-tune blood vessel reactivity. Because the lipid raft localization of ion channels is crucial for cardiovascular physiology, Kv7.1/Kv7.5 heteromers provide efficient spatial and temporal regulation of smooth muscle function. Our results shed light on the debate about the contribution of Kv7 channels to vasoconstriction and hypertension.

Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1

“…The simulated macroscopic current (Figure 5O) displays the two signatures of recorded macroscopic Kv7.1 ionic currents: a short initial delay (5 to 10 ms) and early inactivation. Additionally, the activation duration is consistent with that of the experimentally recorded currents (Oliveras et al, 2014; Shamgar et al, 2008; Wu et al, 2010a; Wu et al, 2010b). …”

Mechanisms of PKA-Dependent Potentiation of Kv7.5 Channel Activity in Human Airway Smooth Muscle Cells

“…The voltage-dependence for activation varies among Kv7 channel subtypes when expressed in mammalian cells, with Kv7.5 activating at more negative voltages than other subtypes. The V 0.5 of activation of HASMC Kv7 currents (−41 mV) is most similar to that reported for cloned Kv7.5 channels expressed in mammalian cells (−44.2 ± 1.7 mV; −46 ± 3 mV [13,17]) and considerably more negative than that of Kv7.4 (−30.6 ± 1.2 mV [13]), or Kv7.3 (−37.3 ± 1.3 mV [18]). All told, the experimental evidence suggests that the endogenous Kv7 currents measured in HASMCs are elicited predominantly via Kv7.5 channels.…”

Activation of Kv7 channels as a novel mechanism for NO/cGMP‐induced pulmonary vasodilation

“…Thus, it is plausible that cGMP may activate K v 7 channels through a PKA‐dependent activation of K v 7 channels (Chambard & Ashmore, ; Mani et al, ). Interestingly, we and other authors have shown that K v 7.5 may form functional heterotetrameric channels with K v 7.1 (Oliveras et al, ) and K v 7.4 (Brueggemann et al, ) in vascular tissues. Thus, it is conceivable that activation of K v 7.1/K v 7.5 or K v 7.4/K v 7.5 heterotetramers could contribute to cGMP‐mediated responses as previously proposed (Stott et al, ).…”