Modulation of the molecular composition of large conductance, Ca(2+) activated K(+) channels in vascular smooth muscle during hypertension.
Hypertension is a clinical syndrome characterized by increased vascular tone. However, the molecular mechanisms underlying vascular dysfunction during acquired hypertension remain unresolved. Localized intracellular Ca2+ release events through ryanodine receptors (Ca2+ sparks) in the sarcoplasmic reticulum are tightly coupled to the activation of large-conductance, Ca2+-activated K+ (BK) channels to provide a hyperpolarizing influence that opposes vasoconstriction. In this study we tested the hypothesis that a reduction in Ca2+ spark-BK channel coupling underlies vascular smooth muscle dysfunction during acquired hypertension. We found that in hypertension, expression of the beta1 subunit was decreased relative to the pore-forming alpha subunit of the BK channel. Consequently, the BK channels were functionally uncoupled from Ca2+ sparks. Consistent with this, the contribution of BK channels to vascular tone was reduced during hypertension. We conclude that downregulation of the beta1 subunit of the BK channel contributes to vascular dysfunction in hypertension. These results support the novel concept that changes in BK channel subunit composition regulate arterial smooth muscle function.
Amberg
Gregory C
GC
Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195, USA.
Bonev
Adrian D
AD
Rossow
Charles F
CF
Nelson
Mark T
MT
Santana
Luis F
LF
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006973:Hypertension / Q000209:etiology / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D021122:Protein Subunits; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D021122:Protein Subunits; D012333:RNA, Messenger; C064719:iberiotoxin; D002118:Calcium