Dynamic regulation of ?1 subunit trafficking controls vascular contractility.

ABSTRACT: Ion channels composed of pore-forming and auxiliary subunits control physiological functions in virtually all cell types. A conventional view is that channels assemble with their auxiliary subunits before anterograde plasma membrane trafficking of the protein complex. Whether the multisubunit composition of surface channels is fixed following protein synthesis or flexible and open to acute and, potentially, rapid modulation to control activity and cellular excitability is unclear. Arterial smooth muscle cells (myocytes) express large-conductance Ca(2+)-activated potassium (BK) channel ? and auxiliary ?1 subunits that are functionally significant modulators of arterial contractility. Here, we show that native BK? subunits are primarily (?95%) plasma membrane-localized in human and rat arterial myocytes. In contrast, only a small fraction (?10%) of total ?1 subunits are located at the cell surface. Immunofluorescence resonance energy transfer microscopy demonstrated that intracellular ?1 subunits are stored within Rab11A-postive recycling endosomes. Nitric oxide (NO), acting via cGMP-dependent protein kinase, and cAMP-dependent pathways stimulated rapid (?1 min) anterograde trafficking of ?1 subunit-containing recycling endosomes, which increased surface ?1 almost threefold. These ?1 subunits associated with surface-resident BK? proteins, elevating channel Ca(2+) sensitivity and activity. Our data also show that rapid ?1 subunit anterograde trafficking is the primary mechanism by which NO activates myocyte BK channels and induces vasodilation. In summary, we show that rapid ?1 subunit surface trafficking controls functional BK channel activity in arterial myocytes and vascular contractility. Conceivably, regulated auxiliary subunit trafficking may control ion channel activity in a wide variety of cell types.

SUBMITTER: Leo MD 

PROVIDER: S-EPMC3926029 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature