Regulation of coronary arterial BK channels by caveolae-mediated angiotensin II signaling in diabetes mellitus.
BACKGROUND
The large conductance Ca(2+)-activated K(+) (BK) channel, a key determinant of vascular tone, is regulated by angiotensin II (Ang II) type 1 receptor signaling. Upregulation of Ang II functions and downregulation of BK channel activities have been reported in diabetic vessels. However, the molecular mechanisms underlying Ang II-mediated BK channel modulation, especially in diabetes mellitus, have not been thoroughly examined.


OBJECTIVE
The aim in this study was to determine whether caveolae-targeting facilitates BK channel dysfunction in diabetic vessels.


RESULTS
Using patch clamp techniques and molecular biological approaches, we found that BK channels, Ang II type 1 receptor, G(alphaq/11) (G protein q/11 alpha subunit), nonphagocytic NAD(P)H oxidases (NOX-1), and c-Src kinases (c-Src) were colocalized in the caveolae of rat arterial smooth muscle cells and the integrity of caveolae in smooth muscle cells was critical for Ang II-mediated BK channel regulation. Most importantly, membrane microdomain targeting of these proteins was upregulated in the caveolae of streptozotocin-induced rat diabetic vessels, leading to enhanced Ang II-induced redox-mediated BK channel modification and causing BK channel and coronary dysfunction. The absence of caveolae abolished the effects of Ang II on vascular BK channel activity and preserved BK channel function in diabetes.


CONCLUSIONS
These results identified a molecular scheme of receptor/enzyme/channel/caveolae microdomain complex that facilitates the development of vascular BK channel dysfunction in diabetes.
Lu
Tong
T
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. lu.tong@mayo.edu
Zhang
Dai-Min
DM
Wang
Xiao-Li
XL
He
Tongrong
T
Wang
Ru-Xing
RX
Chai
Qiang
Q
Katusic
Zvonimir S
ZS
Lee
Hon-Chi
HC
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D021941:Caveolae / Q000378:metabolism*; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074624:NADPH Oxidase 1; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014661:Vasoconstriction; D019061:src-Family Kinases
C495541:Cav1 protein, mouse; C495537:Cav1 protein, rat; D051242:Caveolin 1; D004791:Enzyme Inhibitors; D051036:Large-Conductance Calcium-Activated Potassium Channels; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D011188:Potassium