1. p90 Ribosomal S6 kinases play a significant role in early gene regulation in the cardiomyocyte response to Gq-protein-coupled receptor stimuli, endothelin-1 and α1-adrenergic receptor agonists
- Author
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Emre Amirak, Stephen J. Fuller, Peter H. Sugden, and Angela Clerk
- Subjects
Male ,α1-adrenergic receptor ,GSK3α/β, glycogen synthase kinase 3α/β ,cardiomyocyte ,Olr1, oxidized low-density lipoprotein (lectin-like) receptor 1 ,Biochemistry ,Rats, Sprague-Dawley ,transcriptomics ,CREB, cAMP-response-element-binding protein ,Plk2, polo-like kinase 2 ,AR, adrenergic receptor ,Klf, Krüppel-like factor ,Ptgs2, prostaglandin-endoperoxide synthase 2, qPCR, quantitative PCR ,Gene expression ,SNK, Student–Newman–Keuls ,p90 ribosomal S6 kinase (p90 RSK) ,Egr, early growth response ,MSK, mitogen- and stress-activated protein kinase ,Myocytes, Cardiac ,Receptor ,ERK1/2, extracellular-signal-regulated kinase 1/2 ,Regulation of gene expression ,Areg, amphiregulin ,Mitogen-Activated Protein Kinase 3 ,biology ,Kinase ,Receptor, Endothelin A ,RSK, ribosomal S6 kinase ,Gq alpha subunit ,Benzamides ,Signal transduction ,endothelin ,Adrenergic alpha-Agonists ,NPE, nuclear protein-enriched ,Research Article ,Signal Transduction ,Agonist ,PKB, protein kinase B ,FDR, false discovery rate ,medicine.drug_class ,Dusp, dual-specificity phosphatase ,IL11, interleukin 11 ,MKK, MAPK kinase ,Gapdh, glyceraldehyde 3-phosphate dehydrogenase ,Ribosomal Protein S6 Kinases, 90-kDa ,Lif, leukaemia inhibitory factor ,Receptors, Adrenergic, alpha-1 ,medicine ,ET-1, endothelin-1 ,Animals ,mitogen-activated protein kinase (MAPK) ,Fosb, FBJ murine osteosarcoma viral oncogene homologue B ,Molecular Biology ,Transcription factor ,BH-MTC, Benjamini and Hochberg multiple testing correction ,Cell Nucleus ,Nr4a, nuclear receptor subfamily 4, group A ,PE, phenylephrine ,Cell Biology ,Molecular biology ,Rgs2, regulator of G-protein signalling 2, 24 kDa ,Rats ,Has, hyaluronan synthase ,Atf3, activating transcription factor 3 ,Gene Expression Regulation ,MNK, MAPK-interacting protein kinase ,biology.protein ,AMPKα, AMP-activated protein kinase α ,RNA ,Sik1, salt-inducible kinase 1 ,MAPK, mitogen-activated protein kinase - Abstract
ERK1/2 (extracellular-signal-regulated kinase 1/2) and their substrates RSKs (p90 ribosomal S6 kinases) phosphorylate different transcription factors, contributing differentially to transcriptomic profiles. In cardiomyocytes ERK1/2 are required for >70% of the transcriptomic response to endothelin-1. In the present study we investigated the role of RSKs in the transcriptomic responses to the Gq-protein-coupled receptor agonists endothelin-1, phenylephrine (a generic α1-adrenergic receptor agonist) and A61603 (α1A-adrenergic receptor selective). Phospho-ERK1/2 and phospho-RSKs appeared in cardiomyocyte nuclei within 2–3 min of stimulation (endothelin-1>A61603≈phenylephrine). All agonists increased nuclear RSK2, but only endothelin-1 increased the nuclear RSK1 content. PD184352 (inhibits ERK1/2 activation) and BI-D1870 (inhibits RSKs) were used to dissect the contribution of RSKs to the endothelin-1-responsive transcriptome. Of the 213 RNAs up-regulated after 1 h, 51% required RSKs for their up-regulation, whereas 29% required ERK1/2 but not RSKs. The transcriptomic response to phenylephrine overlapped with, but was not identical with, endothelin-1. As with endothelin-1, PD184352 inhibited the up-regulation of most phenylephrine-responsive transcripts, but the greater variation in the effects of BI-D1870 suggests that differential RSK signalling influences global gene expression. A61603 induced similar changes in RNA expression in cardiomyocytes as phenylephrine, indicating that the signal was mediated largely through α1A-adrenergic receptors. A61603 also increased expression of immediate early genes in perfused adult rat hearts and, as in cardiomyocytes, up-regulation of the majority of genes was inhibited by PD184352. PD184352 or BI-D1870 prevented the increased surface area induced by endothelin-1 in cardiomyocytes. Thus RSKs play a significant role in regulating cardiomyocyte gene expression and hypertrophy in response to Gq-protein-coupled receptor stimulation.
- Published
- 2013