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Adenosine A(1) receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle
Adenosine receptors (AR; A(1), A(2A), A(2B), and A(3)) contract and relax smooth muscle through different signaling mechanisms. Deciphering these complex responses remains difficult because relationships between AR subtypes and various end-effectors (e.g., enzymes and ion channels) remain to be iden...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747964/ https://www.ncbi.nlm.nih.gov/pubmed/23977428 http://dx.doi.org/10.1002/phy2.37 |
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author | Kunduri, S S Dick, G M Nayeem, M A Mustafa, S J |
author_facet | Kunduri, S S Dick, G M Nayeem, M A Mustafa, S J |
author_sort | Kunduri, S S |
collection | PubMed |
description | Adenosine receptors (AR; A(1), A(2A), A(2B), and A(3)) contract and relax smooth muscle through different signaling mechanisms. Deciphering these complex responses remains difficult because relationships between AR subtypes and various end-effectors (e.g., enzymes and ion channels) remain to be identified. A(1)AR stimulation is associated with the production of 20–hydroxyeicosatetraenoic acid (20–HETE) and activation of protein kinase C (PKC). 20–HETE and PKC can inhibit large conductance Ca(2+)/voltage-sensitive K(+) (BK) channels that regulate smooth muscle contraction. We tested the hypothesis that activation of A(1)AR inhibits BK channels via a PKC-dependent mechanism. Patch clamp recordings and Western blots were performed using aortae of wild type (WT) and A(1)AR knockout (A(1)KO) mice. There were no differences in whole-cell K(+) current or α and β1 subunits expression between WT and A(1)KO. 20–HETE (100 nmol/L) inhibited BK current similarly in WT and A(1)KO mice. NECA (5′–N–ethylcarboxamidoadenosine; 10 μmol/L), a nonselective AR agonist, increased BK current in myocytes from both WT and A(1)KO mice, but the increase was greater in A(1)KO (52 ± 15 vs. 17 ± 3%; P < 0.05). This suggests that A(1)AR signaling negatively regulates BK channel activity. Accordingly, CCPA (2–chloro–N(6)-cyclopentyladenosine; 100 nmol/L), an A(1)AR-selective agonist, inhibited BK current in myocytes from WT but not A(1)KO mice (81 ± 4 vs. 100 ± 7% of control; P < 0.05). Gö6976 (100 nmol/L), a PKCα inhibitor, abolished the effect of CCPA to inhibit BK current (99 ± 3% of control). These data lead us to conclude that, in aortic smooth muscle, A(1)AR inhibits BK channel activity and that this occurs via a mechanism involving PKCα. |
format | Online Article Text |
id | pubmed-3747964 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-37479642013-12-03 Adenosine A(1) receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle Kunduri, S S Dick, G M Nayeem, M A Mustafa, S J Physiol Rep Original Research Adenosine receptors (AR; A(1), A(2A), A(2B), and A(3)) contract and relax smooth muscle through different signaling mechanisms. Deciphering these complex responses remains difficult because relationships between AR subtypes and various end-effectors (e.g., enzymes and ion channels) remain to be identified. A(1)AR stimulation is associated with the production of 20–hydroxyeicosatetraenoic acid (20–HETE) and activation of protein kinase C (PKC). 20–HETE and PKC can inhibit large conductance Ca(2+)/voltage-sensitive K(+) (BK) channels that regulate smooth muscle contraction. We tested the hypothesis that activation of A(1)AR inhibits BK channels via a PKC-dependent mechanism. Patch clamp recordings and Western blots were performed using aortae of wild type (WT) and A(1)AR knockout (A(1)KO) mice. There were no differences in whole-cell K(+) current or α and β1 subunits expression between WT and A(1)KO. 20–HETE (100 nmol/L) inhibited BK current similarly in WT and A(1)KO mice. NECA (5′–N–ethylcarboxamidoadenosine; 10 μmol/L), a nonselective AR agonist, increased BK current in myocytes from both WT and A(1)KO mice, but the increase was greater in A(1)KO (52 ± 15 vs. 17 ± 3%; P < 0.05). This suggests that A(1)AR signaling negatively regulates BK channel activity. Accordingly, CCPA (2–chloro–N(6)-cyclopentyladenosine; 100 nmol/L), an A(1)AR-selective agonist, inhibited BK current in myocytes from WT but not A(1)KO mice (81 ± 4 vs. 100 ± 7% of control; P < 0.05). Gö6976 (100 nmol/L), a PKCα inhibitor, abolished the effect of CCPA to inhibit BK current (99 ± 3% of control). These data lead us to conclude that, in aortic smooth muscle, A(1)AR inhibits BK channel activity and that this occurs via a mechanism involving PKCα. Blackwell Publishing Ltd 2013-08 2013-07-29 /pmc/articles/PMC3747964/ /pubmed/23977428 http://dx.doi.org/10.1002/phy2.37 Text en © 2013 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Original Research Kunduri, S S Dick, G M Nayeem, M A Mustafa, S J Adenosine A(1) receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle |
title | Adenosine A(1) receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle |
title_full | Adenosine A(1) receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle |
title_fullStr | Adenosine A(1) receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle |
title_full_unstemmed | Adenosine A(1) receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle |
title_short | Adenosine A(1) receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle |
title_sort | adenosine a(1) receptor signaling inhibits bk channels through a pkcα-dependent mechanism in mouse aortic smooth muscle |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747964/ https://www.ncbi.nlm.nih.gov/pubmed/23977428 http://dx.doi.org/10.1002/phy2.37 |
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