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LRRC26 is a functional BK channel auxiliary ? subunit in arterial smooth muscle cells.

ABSTRACT: Smooth muscle cell (myocyte) large-conductance calcium (Ca)(2+)-activated potassium (BK) channels are functionally significant modulators of arterial contractility. Arterial myocytes express both pore-forming BK? and auxiliary ?1 subunits, which increase channel Ca(2+) sensitivity. Recently, several leucine-rich repeat containing (LRRC) proteins have been identified as auxiliary ? subunits that elevate the voltage sensitivity of recombinant and prostate adenocarcinoma BK channels. LRRC expression and physiological functions in native cell types are unclear.Investigate the expression and physiological functions of leucine-rich repeat containing protein 26 (LRRC26) in arterial myocytes.Reverse transcription polymerase chain reaction and Western blotting detected LRRC26 mRNA and protein in cerebral artery myocytes. Biotinylation, immunofluorescence resonance energy transfer microscopy, and coimmunoprecipitation indicated that LRRC26 was located in close spatial proximity to, and associated with, plasma membrane BK? subunits. LRRC26 knockdown (RNAi) reduced total and surface LRRC26, but did not alter BK? or ?1, proteins in arteries. LRRC26 knockdown did not alter Ca(2+) sparks but reduced BK channel voltage sensitivity, which decreased channel apparent Ca(2+) sensitivity and transient BK current frequency and amplitude in myocytes. LRRC26 knockdown also increased myogenic tone over a range (40-100 mm Hg) of intravascular pressures, and reduced vasoconstriction to iberiotoxin and vasodilation to NS1619, BK channel inhibitors and activators, respectively. In contrast, LRRC26 knockdown did not alter depolarization (60 mmol/L K(+))-induced vasoconstriction.LRRC26 is expressed, associates with BK? subunits, and elevates channel voltage- and apparent Ca(2+) sensitivity in arterial myocytes to induce vasodilation. This study indicates that arterial myocytes express a functional BK channel ? subunit.

SUBMITTER: Evanson KW

PROVIDER: S-EPMC4119551 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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LRRC26 is a functional BK channel auxiliary γ subunit in arterial smooth muscle cells.

Evanson Kirk W KW Bannister John P JP Leo M Dennis MD Jaggar Jonathan H JH

Circulation research 20140606 4

<h4>Rationale</h4>Smooth muscle cell (myocyte) large-conductance calcium (Ca)(2+)-activated potassium (BK) channels are functionally significant modulators of arterial contractility. Arterial myocytes express both pore-forming BKα and auxiliary β1 subunits, which increase channel Ca(2+) sensitivity. Recently, several leucine-rich repeat containing (LRRC) proteins have been identified as auxiliary γ subunits that elevate the voltage sensitivity of recombinant and prostate adenocarcinoma BK channe ...[more]

PMID: 24906643

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Project description:Aims:Type 2 diabetes (T2D) is strongly associated with cardiovascular morbidity and mortality in patients. Vascular large conductance Ca2+-activated potassium (BK) channels, composed of four pore-forming ? subunits (BK-?), and four regulatory ?1 subunits (BK-?1), are densely expressed in coronary arterial smooth muscle cells (SMCs) and play an important role in regulating vascular tone and myocardial perfusion. However, the role of BK channels in coronary microvascular dysfunction of human subjects with diabetes is unclear. In this study, we examined BK channel function and protein expression, and BK channel-mediated vasodilation in freshly isolated coronary arterioles from T2D patients. Methods and results:Atrial tissues were obtained from 16 patients with T2D and 25 matched non-diabetic subjects during cardiopulmonary bypass procedure. Microvessel videomicroscopy and immunoblot analysis were performed in freshly dissected coronary arterioles and inside-out single BK channel currents was recorded in enzymatically isolated coronary arteriolar SMCs. We found that BK channel sensitivity to physiological Ca2+ concentration and voltage was downregulated in the coronary arteriolar SMCs of diabetic patients, compared with non-diabetic controls. BK channel kinetics analysis revealed that there was significant shortening of the mean open time and prolongation of the mean closed time in diabetic patients, resulting in a remarkable reduction of the channel open probability. Functional studies showed that BK channel activation by dehydrosoyasaponin-1 was diminished and that BK channel-mediated vasodilation in response to shear stress was impaired in diabetic coronary arterioles. Immunoblot experiments confirmed that the protein expressions of BK-? and BK-?1 subunits were significantly downregulated, but the ratio of BK-?/BK-?1 was unchanged in the coronary arterioles of T2D patients. Conclusions:Our results demonstrated for the first time that BK channel function and BK channel-mediated vasodilation were abnormal in the coronary microvasculature of diabetic patients, due to decreased protein expression and altered intrinsic properties of BK channels.

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LRRC26 is a functional BK channel auxiliary ? subunit in arterial smooth muscle cells.

Publications

LRRC26 is a functional BK channel auxiliary γ subunit in arterial smooth muscle cells.

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