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Angiotensin II Stimulates Internalization and Degradation of BK Channels in Arterial Myocytes to Induce Vasoconstriction

Arterial myocytes express large‐conductance Ca2+‐activated (BK) channel α and auxiliary β1 subunits that are functionally significant modulators of arterial contractility. Previously, we showed that native BKα subunits are primarily (~95%) plasma membrane‐localized, whereas β1 subunits are stored within rab11A‐positive recycling endosomes that are stimulated by nitric oxide (NO) to rapidly (<1 min) traffic to the plasma membrane (Leo et al., PNAS 2014). Here, using biotinylation, immuno‐FRET microscopy, RNAi‐mediated knockdown and rab4A dominant‐negative mutants, we demonstrate that rab4A‐positive early endosomes traffic BKα to the plasma membrane in myocytes of resistance‐size cerebral arteries. Angiotensin II (ang II) stimulated slow (hours), PKC‐dependent internalization followed by lysosomal and proteosomal degradation of BKα. In the presence of ang II, lysosomal and proteosomal degradation inhibitors retained BKα at the surface, indicating that ang II did not affect anterograde BKα trafficking. Angiotensin II treatment inhibited BK currents in isolated myocytes and decreased constriction to iberiotoxin, a BK blocker, and dilation to NS1619, a BK activator, in pressurized (60 mmHg) cerebral arteries. In summary, we show that rab4A‐positive early endosomes traffic BKα to the plasma membrane and that prolonged angiotensin II exposure stimulates BKα internalization and degradation, leading to a reduction in BK currents and vasoconstriction.