Abstract
Adenylyl cyclases (ACs) catalyze the conversion of ATP into the second messenger cAMP. Membranous AC1 (AC1) is involved in processes of memory and learning and in muscle pain. The AC toxin edema factor (EF) of Bacillus anthracis is involved in the development of anthrax. Both ACs are stimulated by the eukaryotic Ca2+-sensor calmodulin (CaM). The CaM-AC interaction could constitute a potential target to enhance or impair the AC activity of AC1 and EF to intervene in above (patho)physiological mechanisms. Thus, we analyzed the impact of 39 compounds including typical CaM-inhibitors, an anticonvulsant, an anticholinergic, antidepressants, antipsychotics and Ca2+-antagonists on CaM-stimulated catalytic activity of AC1 and EF. Compounds were tested at 10 μM, i.e., a concentration that can be reached therapeutically for certain antidepressants and antipsychotics. Calmidazolium chloride decreased CaM-stimulated AC1 activity moderately by about 30%. In contrast, CaM-stimulated EF activity was abrogated by calmidazolium chloride and additionally decreased by chlorpromazine, felodipine, penfluridol and trifluoperazine by about 20–40%. The activity of both ACs was decreased by calmidazolium chloride in the presence and absence of CaM. Thus, CaM-stimulated AC1 activity is more insensitive to inhibition by small molecules than CaM-stimulated EF activity. Inhibition of AC1 and EF by calmidazolium chloride is largely mediated via a CaM-independent allosteric mechanism.
Highlights
Adenylyl cyclases (AC) catalyze the conversion of ATP into the second messenger cAMP, which is involved in the regulation of numerous processes such as hormone secretion and cardiac contractility [1, 2]
The different CaM-concentrations used for AC isoform 1 (AC1) and edema factor (EF) are caused by their different CaM-affinities
In contrast to numerous previous studies analyzing the effect of CaM-inhibitors on CaMtarget interactions using extremely high concentrations of up to 1000 μ M of CaM-inhibitors (Table 1), a cut-off concentration of 10 μM of each small molecule was chosen for analyses presented in this study
Summary
Adenylyl cyclases (AC) catalyze the conversion of ATP into the second messenger cAMP, which is involved in the regulation of numerous processes such as hormone secretion and cardiac contractility [1, 2]. AC1 is expressed in brain and is involved in physiological processes of memory and learning [4,5,6,7,8,9]. Bacillus anthracis is the causative agent of anthrax, a potentially lethal infectious disease. The AC toxin edema factor, released by Bacillus anthracis during infection, is involved in the pathogenesis of anthrax and facilitates bacterial growth via inhibiting the innate immune system by generating extremely high cAMP levels [10,11,12].
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