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CARDIOVASCULAR

Functional Adenylyl Cyclase Inhibition in Murine Cardiomyocytes by 2'(3')-O-(N-Methylanthraniloyl)-Guanosine 5'-[-Thio]triphosphate

Department of Pharmacology (D.R., J.M., S.H.) and Center for Molecular Medicine (S.H.), University of Cologne, Köln, Germany; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey (S.F.V.); and Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (R.S.)

₁-Adrenergic receptor activation stimulates cardiac L-type Ca²⁺ channels via adenylyl cyclases (ACs), with AC5 and AC6 being the most important cardiac isoforms. Recently, we have identified 2'(3')-O-(N-methylanthraniloyl)-guanosine 5'-[-thio-]triphosphate (MANT-GTPS) as a potent competitive AC inhibitor. Intriguingly, MANT-GTPS inhibits AC5 and -6 more potently than other cyclases. These data prompted us to study the effects of MANT-GTPS on L-type Ca²⁺ currents (I_Ca,L) in ventricular myocytes of wild-type (WT) and AC5-deficient (AC5^–/–) mice by whole-cell recordings. In wild-type myocytes, MANT-GTPS attenuated I_Ca,L stimulation following isoproterenol application in a concentration-dependent manner (control, +77 ± 13%; 100 nM MANT-GTPS, +43 ± 6%; 1 µM MANT-GTPS, +21 ± 9%; p < 0.05). The leftward shift of current-voltage curves was abolished by 1 µM but not by 100 nM MANT-GTPS. In myocytes from AC5^–/– mice, the residual stimulation of I_Ca,L was not further attenuated by the nucleotide, indicating AC5 to be the major AC isoform mediating acute -adrenergic stimulation in WT mice. Interestingly, basal I_Ca,L was lowered by 1 µM but not by 100 nM MANT-GTPS. The decrease was less pronounced in myocytes from AC5^–/– mice compared with wild types (–23 ± 1 versus –40 ± 7%), indicating basal I_Ca,L to be partly driven by AC5. Collectively, we found a concentration-dependent inhibition of I_Ca,L by MANT-GTPS, both under basal conditions and following -adrenergic stimulation. Comparison of data from wild-type and AC5-deficient mice indicates that AC5 plays a major role in I_Ca,L activation and that MANT-GTPS predominantly acts via AC5 inhibition.

Address correspondence to: Dr. Stefan Herzig, Department of Pharmacology, University of Cologne, Gleueler Str. 24, D-50931 Köln, Germany. E-mail: stefan.herzig{at}uni-koeln.de

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