Objectives: 

Voltage-dependent K+ channels (Kv) from the Kv7 family are implicated in modulating vascular smooth-muscle tone. Specifically, Kv7.1, Kv7.4 and Kv7.5 are expressed in blood vessels and contribute to cardiovascular physiology. While Kv7 channel blockers trigger muscle contractions, Kv7 channel activators act as vasorelaxants. Although Kv7.1 is highly expressed in many vessels, Kv7.1 blockers fail to modulate smooth-muscle reactivity. For this reason, the role of the Kv7.1 channel is under intense investigation. Neuronal Kv7 channels form heterotetramers, whereas Kv7.1 association is notably restricted.

Materials: 

We performed electrophysiological and pharmacological studies in Xenopus oocytes, and confocal microscopy and lipid raft isolation in HEK-293 cells and myoblasts.

Results: 

In this study, we demonstrate that Kv7.1 and Kv7.5 can form functional heterotetrameric channels. The hybrid Kv7.1/Kv7.5 structures have a characteristic phenotype. Similar to Kv7.1, Kv7.1/Kv7.5 heteromeric channels are highly retained at the endoplasmic reticulum. However, studies in heart, myoblasts and HEK-293 cells demonstrate that unlike Kv7.1, the presence of Kv7.5 stimulates release of Kv7.1/Kv7.5 oligomers out of lipid rafts.

Conclusions: 

Because the lipid raft localization of ion channels is crucial for cardiovascular physiology, we propose that the formation of Kv7.1/Kv7.5 heteromeric channels provides efficient spatial and temporal regulation of smooth-muscle cell function. Our results shed light on the debate regarding the relative contribution of Kv7 channels to vasoconstriction and hypertension.

Supported by BFU2011-23268 and CSD2008-00005 to AF (MINECO, Spain).