Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
PLoS One. 2013 Jul 1;8(7):e68009. doi: 10.1371/journal.pone.0068009. Print 2013.
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.
腺苷酸环化酶 5（AC5）被描述为主要的心脏 AC 同工酶。AC5 的敲除（AC5KO）在心衰中发挥了心脏保护作用。我们的研究探讨了 AC5KO 对小鼠心脏 AC 活性的影响，并评估了潜在的 AC5 选择性抑制剂。在 AC5KO 小鼠的心脏膜中，基础 AC 活性降低，而 AC 刺激仍然完整。假定的 AC5 选择性 P 位抑制剂 SQ22,536[9-（四氢-2-呋喃基）-9H-嘌呤-6-胺]、阿糖腺苷（9-β-D-阿拉伯呋喃糖基腺嘌呤）和 NKY80[2-氨基-7-（2-呋喃基）-7,8-二氢-5(6H)-喹唑啉酮]比 AC2 和 AC1 更有效地抑制重组 AC5，但选择性仅适中（约 4-40 倍）。这些化合物以相似的效力抑制 WT 和 AC5KO 小鼠的心脏 AC。总之，AC5KO 心脏中的 AC 调节不受影响，这对 AC5 在心脏中的主导作用提出了质疑。此外，AC 抑制剂 SQ22,536、NKY80 和阿糖腺苷对 AC5 缺乏足够的选择性，因此不适合作为研究 AC5 特异性功能的工具。
