Huebner, Melanie and Dizayee, Sara and Matthes, Jan and Seifert, Roland and Herzig, Stefan (2011) Effect of MANT-nucleotides on L-type calcium currents in murine cardiomyocytes. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 383 (6). pp. 573-583. ISSN 0028-1298,
Full text not available from this repository. (Request a copy)Abstract
Membranous adenylyl cyclases play a major role in G-protein-coupled receptor signalling and regulate various cellular responses, such as cardiac contraction. Cardiac apoptosis and development of cardiac dysfunction is prevented in mice lacking AC 5, a predominant isoform in the heart. In the search for a potent and selective AC 5 inhibitor, we recently identified 2'(3')-methylanthraniloyl-inosine-5'-triphosphate(MANT-ITP) as the most potent AC 5 inhibitor with a K (i) of 13 nM. Therefore, AC inhibition of MANT-ITP was assessed in ventricular cardiomyocytes and compared to three other MANT-nucleotides to evaluate its effect on cardiac signalling. Basal and isoproterenol-induced L-type calcium currents (I (Ca,L)) in murine ventricular cardiomyocytes were recorded by whole-cell patch-clamp technique, using four different MANT-nucleotides. The effects of the MANT-nucleotides on I (Ca,L) were unexpectedly complex. All MANT-nucleotides exhibited an inhibitory effect on basal I (Ca,L). Additionally, several MANT-nucleotides, i.e., MANT-ITP gamma S, MANT-ATP, and MANT-ITP, caused a strong initial increase in basal I (Ca,L) within the first 2.5 min that appeared to be unrelated to AC 5 inhibition. However, we detected a significant reduction on isoproterenol-induced I (Ca,L) with MANT-ITP, supporting the notion that AC 5 plays an important role in agonist-stimulated activation of I (Ca,L). Collectively, MANT-nucleotides are useful tools for the characterization of recombinant ACs, for fluorescence studies and crystallography, but in intact cardiomyocytes, caution must be exerted since MANT-nucleotides apparently possess additional effects than AC 5 inhibition, limiting their usefulness as tools for intact cell studies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ADENYLYL-CYCLASE ISOFORMS; CYCLIC-GMP; PYRIMIDINE NUCLEOTIDES; GUANINE-NUCLEOTIDES; FORSKOLIN ANALOGS; HEART-FAILURE; INHIBITION; DISRUPTION; PURINE; 2'(3')-O-(N-METHYLANTHRANILOYL)-GUANOSINE; MANT-nucleotides; AC inhibition; Cardiomyocytes; Whole-cell patch clamp; L-type calcium current; Isoproterenol |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Jun 2020 14:22 |
| Last Modified: | 15 Jun 2020 14:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/20786 |
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