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Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Cell+Physiol 2015 ; 309 (6): C392-402 Nephropedia Template TP
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Angiotensin II stimulates internalization and degradation of arterial myocyte plasma membrane BK channels to induce vasoconstriction #MMPMID26179602
Am J Physiol Cell Physiol 2015[Sep]; 309 (6): C392-402 PMID26179602show ga
Arterial smooth muscle cells (myocytes) express large-conductance Ca2+-activated K+ (BK) channel ? and auxiliary ?1 subunits that modulate arterial contractility. In arterial myocytes, ?1 subunits are stored within highly mobile rab11A-positive recycling endosomes. In contrast, BK? subunits are primarily plasma membrane-localized. Trafficking pathways for BK? and whether physiological stimuli that regulate arterial contractility alter BK? localization in arterial myocytes are unclear. Here, using biotinylation, immunofluorescence resonance energy transfer (immunoFRET) microscopy, and RNAi-mediated knockdown, we demonstrate that rab4A-positive early endosomes traffic BK? to the plasma membrane in myocytes of resistance-size cerebral arteries. Angiotensin II (ANG II), a vasoconstrictor, reduced both surface and total BK?, an effect blocked by bisindolylmaleimide-II, concanavalin A, and dynasore, protein kinase C (PKC), internalization, and endocytosis inhibitors, respectively. In contrast, ANG II did not reduce BK? mRNA, and sodium nitroprusside, a nitric oxide donor, did not alter surface BK? protein over the same time course. MG132 and bafilomycin A, proteasomal and lysosomal inhibitors, respectively, also inhibited the ANG II-induced reduction in surface and total BK?, resulting in intracellular BK? accumulation. ANG II-mediated BK channel degradation reduced BK currents in isolated myocytes and functional responses to iberiotoxin, a BK channel blocker, and NS1619, a BK activator, in pressurized (60 mmHg) cerebral arteries. These data indicate that rab4A-positive early endosomes traffic BK? to the plasma membrane in arterial myocytes. We also show that ANG II stimulates PKC-dependent BK? internalization and degradation. These data describe a unique mechanism by which ANG II inhibits arterial myocyte BK currents, by reducing surface channel number, to induce vasoconstriction.