title: Antagonism of estrogen receptor and calmodulin association by antiestrogens is not dependent on an interaction with calmodulin.
abstract: Previously, two antiestrogens estradiol derivatives (3 and 4) bearing the basic side chain of tamoxifen were shown to impede the binding of the estrogen receptor (ER) to calmodulin (CaM)-Sepharose. In this study, the interaction of these and related compounds with calmodulin was examined using the cyclic AMP phosphodiesterase (cAMP-PDE) assay. Neither of the steroids gave any significant inhibition of the calmodulin dependent cAMP-PDE activity up to a final concentration of 20 microM. For comparison, tamoxifen and nafoxidine produced IC50 values of 6.7 microM +/- 1.0 and 7.4 microM +/- 1.1, respectively. In addition, a comparison was made of the activity of some triphenylethylene derivatives against CaM dependent cAMP-PDE and the ER-CaM Sepharose assays, but no relationship was observed. Overall, these results demonstrate that inhibition of the ER-CaM association by various steroidal and triphenylethylene antiestrogens does not relate to antagonism of calmodulin function or their binding affinity for the estrogen receptor.
authors.affiliation: Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, CRC Laboratory, Belmont, Sutton, Surrey, U.K.
authors.forename: M G
authors.initials: MG
authors.lastname: Rowlands
authors.forename: R
authors.initials: R
authors.lastname: Grimshaw
authors.forename: M
authors.initials: M
authors.lastname: Jarman
authors.forename: A
authors.initials: A
authors.lastname: Bouhoute
authors.forename: G
authors.initials: G
authors.lastname: Leclercq
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004965:Estrogen Antagonists / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002147:Calmodulin; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1