Adenosine A1 Receptors Link to Smooth Muscle Contraction Via CYP4a, protein kinase C-α, and ERK1/2
Open accessAbstract
Adenosine A1 receptor (A1AR) activation contracts smooth muscle, although signaling mechanisms are not thoroughly understood. Activation of A1AR leads to metabolism of arachidonic acid, including the production of 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P4504a (CYP4a). The 20-HETE can activate protein kinase C-α (PKC-α), which crosstalks with extracellular signal-regulated kinase (ERK1/2) pathway. Both these pathways can regulate smooth muscle contraction, we tested the hypothesis that A1AR contracts smooth muscle through a pathway involving CYP4a, PKC-α, and ERK1/2. Experiments included isometric tension recordings of aortic contraction and Western blots of signaling molecules in wild type (WT) and A1AR knockout (A1KO) mice. Contraction to the A1-selective agonist 2-chloro-N cyclopentyladenosine (CCPA) was absent in A1KO mice aortae, indicating the contractile role of A1AR. Inhibition of CYP4a (HET0016) abolished 2-chloro-N cyclopentyladenosine-induced contraction in WT aortae, indicating a critical role for 20-HETE. Both WT and A1KO mice aortae contracted in response to exogenous 20-HETE. Inhibition of PKC-α (Gö6976) or ERK1/2 (PD98059) attenuated 20-HETE-induced contraction equally, suggesting that ERK1/2 is downstream of PKC-α. Contractions to exogenous 20-HETE were significantly less in A1KO mice; reduced protein levels of PKC-α, p-ERK1/2, and total ERK1/2 supported this observation. Our data indicate that A1AR mediates smooth muscle contraction via CYP4a and a PKC-α-ERK1/2 pathway.
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- Authors
- Kunduri, S. S., Mustafa, S. J., Ponnoth, D. S., Dick, G. M., & Nayeem, M. A.
- Affiliations
- West Virginia University (US)
- Corresponding author
- Kunduri, Swati S.
- Mustafa, S. Jamal
- Ponnoth, Dovenia S.
- Nayeem, Mohammed A.
- Venue
- Journal of Cardiovascular Pharmacology
- Published
- 2013-07
- Volume
- 62
- Issue
- 1
- Pages
- 78-83
- ISSN
- 0160-2446 (ISSN-L)
- PMC
- PMC3710297
- OpenAlex
- W1996717552
- Semantic Scholar
- 06c68bb4a994c98323e576fbdc239b44caaa8720
- Cited by
- 30
- References
- 46
- Citations by year
- 2025: 2 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 6 · 2014: 1 · 2013: 1
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cardiovascular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 027339, R01HL094447, R01HL027339, HL094447)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Keywords
- adenosine A1 receptor, smooth muscle contraction, 20-hydroxyeicosatetraenoic acid, CYP4A, protein kinase C alpha, ERK1/2, signaling crosstalk, aortic contraction, arachidonic acid metabolism
- MeSH terms
- Adenosine, Animals, Carbazoles, Enzyme Inhibitors, Female, Flavonoids, Hydroxyeicosatetraenoic Acids, Isometric Contraction, Male, Mice, Inbred C57BL, Muscle Contraction, Muscle, Smooth, Vascular, Blotting, Western, Mice, Knockout, MAP Kinase Signaling System, Cytochrome P-450 CYP4A, Receptor, Adenosine A1, Mice, Protein Kinase C-alpha, Adenosine A1 Receptor Agonists
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