Vasodilators mobilize SK3 channels in endothelial cells to produce arterial relaxation.

Dieniffer Peixoto-Neves, Shambhu Yadav, Charles E MacKay, Ulrich C Mbiakop, Alejandro Mata-Daboin, M Dennis Leo, Jonathan H Jaggar

Proceedings of the National Academy of Sciences of the United States of America 2023 Aug

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Endothelial cells (ECs) line the lumen of all blood vessels and regulate functions, including contractility. Physiological stimuli, such as acetylcholine (ACh) and intravascular flow, activate transient receptor potential vanilloid 4 (TRPV4) channels, which stimulate small (SK3)- and intermediate (IK)-conductance Ca2+-activated potassium channels in ECs to produce vasodilation. Whether physiological vasodilators also modulate the surface abundance of these ion channels in ECs to elicit functional responses is unclear. Here, we show that ACh and intravascular flow stimulate rapid anterograde trafficking of an intracellular pool of SK3 channels in ECs of resistance-size arteries, which increases surface SK3 protein more than two-fold. In contrast, ACh and flow do not alter the surface abundance of IK or TRPV4 channels. ACh triggers SK3 channel trafficking by activating TRPV4-mediated Ca2+ influx, which stimulates Rab11A, a Rab GTPase associated with recycling endosomes. Superresolution microscopy data demonstrate that SK3 trafficking specifically increases the size of surface SK3 clusters which overlap with TRPV4 clusters. We also show that Rab11A-dependent trafficking of SK3 channels is an essential contributor to vasodilator-induced SK current activation in ECs and vasorelaxation. In summary, our data demonstrate that vasodilators activate Rab11A, which rapidly delivers an intracellular pool of SK3 channels to the vicinity of surface TRPV4 channels in ECs. This trafficking mechanism increases surface SK3 cluster size, elevates SK3 current density, and produces vasodilation. These data also demonstrate that SK3 and IK channels are differentially regulated by trafficking-dependent and -independent signaling mechanisms in endothelial cells.

Citation

Dieniffer Peixoto-Neves, Shambhu Yadav, Charles E MacKay, Ulrich C Mbiakop, Alejandro Mata-Daboin, M Dennis Leo, Jonathan H Jaggar. Vasodilators mobilize SK3 channels in endothelial cells to produce arterial relaxation. Proceedings of the National Academy of Sciences of the United States of America. 2023 Aug;120(31):e2303238120