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.
Highlights
Signaling via the b1-adrenoreceptor (b-AR)-stimulatory Gprotein (Gs)- adenylyl cyclase (AC) cascade is the major mechanism to acutely improve cardiac performance [1]
All other membranous ACs were expressed in AC5 knockout (AC5KO) hearts, and there were no differences between wild type (WT) and AC5KO mice (Fig. 1A)
Analysis of b-ARs and G-proteins did not reveal any altered expression in left ventricles (LVs) samples from AC5KO mice as well (Fig. 1B). Quantitative Reverse Transcription PCR (qRT-PCR) amplifications for AC2 and AC8 exhibited high Ct-values suggesting that mRNA expression of these isoforms was low
Summary
Signaling via the b1-adrenoreceptor (b-AR)-stimulatory Gprotein (Gs)- adenylyl cyclase (AC) cascade is the major mechanism to acutely improve cardiac performance [1]. Upon stimulation by b1-ARs, ACs synthesize the second messenger cAMP, which activates protein kinase A and subsequently leads to the phosphorylation of proteins regulating cardiac excitationcontraction coupling [1]. In acute heart failure (HF), signaling via b1-ARs is increased and initially preserves cardiac function, but its long-term activation in chronic HF promotes disease progression [2]. The treatment of chronic HF with b1-AR antagonists reduces morbidity and mortality, while positive inotropic drugs that increase b-AR signaling or cAMP levels such as catecholamines or phosphodiesterase inhibitors are detrimental [2,3]. AC5 inhibition could constitute an approach for the treatment of heart failure [2,3,4,5,6]
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