Similarly potent inhibition of adenylyl cyclase by P-site inhibitors in hearts from wild type and AC5 knockout mice

PLoS One. 2013 Jul 1;8(7):e68009. doi: 10.1371/journal.pone.0068009. Print 2013.

Abstract

Adenylyl cyclase type 5 (AC5) was described as major cardiac AC isoform. The knockout of AC5 (AC5KO) exerted cardioprotective effects in heart failure. Our study explored the impact of AC5KO on mouse heart AC activities and evaluated putative AC5-selective inhibitors. In cardiac membranes from AC5KO mice, basal AC activity was decreased, while AC stimulation was intact. The putative AC5-selective P-site inhibitors SQ22,536 [9-(tetra-hydro-2-furanyl)-9H-purin-6-amine], vidarabine (9-β-D-arabinosyladenine) and NKY80 [2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone] inhibited recombinant AC5 more potently than AC2 and AC1, but selectivity was only modest (∼4-40-fold). These compounds inhibited cardiac AC from WT and AC5KO mice with similar potencies. In conclusion, AC regulation in AC5KO hearts was unimpaired, questioning the supposed dominant role of AC5 in the heart. Moreover, the AC inhibitors SQ22,536, NKY80 and vidarabine lack adequate selectivity for AC5 and, therefore, do not present suitable tools to study AC5-specific functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclase Inhibitors*
  • Adenylyl Cyclases / genetics*
  • Adenylyl Cyclases / metabolism
  • Animals
  • Cell Line
  • Enzyme Inhibitors / pharmacology*
  • Heart / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / enzymology
  • Myocardium / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism

Substances

  • Adenylyl Cyclase Inhibitors
  • Enzyme Inhibitors
  • Recombinant Proteins
  • Adenylyl Cyclases
  • adenylyl cyclase type V

Grant support

This work was supported by Deutsche Forschungsgemeinschaft grant 529/5-2 to RS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.