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 Ca(2+)-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 Ca(2+)-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.