Kir6.1‐dependent K ATP channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain‐of‐function

• Published in: The Journal of physiology Vol. 598; no. 15; pp. 3107 - 3127
• Main Authors: Davis, Michael J., Kim, Hae Jin, Zawieja, Scott D., Castorena‐Gonzalez, Jorge A., Gui, Peichun, Li, Min, Saunders, Brian T., Zinselmeyer, Bernd H., Randolph, Gwendalyn J., Remedi, Maria S., Nichols, Colin G.
• Format: Journal Article
• Language: English
• Published: England 01.08.2020
• Subjects: Adenosine Triphosphate; Animals; Gain of Function Mutation; Humans; Hypertrichosis; KATP Channels - genetics; Mice; Mice, Inbred C57BL; Muscle, Smooth; Sulfonylurea Receptors - genetics; cantú syndrome; lymphatic dysfunction; pressure myography; electrophysiology; lymphedema
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP279612

Spontaneous contractions are essential for normal lymph transport and these contractions are exquisitely sensitive to the K ATP channel activator pinacidil. K ATP channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional K ATP channels as verified by electrophysiological techniques. Global deletion of Kir6.1 or SUR2 subunits results in severely impaired lymphatic contractile responses to pinacidil. Smooth muscle‐specific expression of Kir6.1 gain‐of‐function mutant (GoF) subunits results in profound lymphatic contractile dysfunction and LSM hyperpolarization that is partially rescued by the K ATP inhibitor glibenclamide. In contrast, lymphatic endothelial‐specific expression of Kir6.1 GoF has essentially no effect on lymphatic contractile function. The high sensitivity of LSM to K ATP channel GoF offers an explanation for the lymphoedema observed in patients with Cantú syndrome, a disorder caused by gain‐of‐function mutations in genes encoding Kir6.1 or SUR2, and suggests that glibenclamide may be an appropriate therapeutic agent.