title: Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1).
abstract: Ryanodine receptor isoforms are expressed in both excitable and nonexcitable tissues where they form microsomal Ca2+ release channels broadly involved in shaping cellular signaling. In this report, we provide a detailed structure-activity relationship (SAR) for polychlorinated biphenyl (PCB) congeners and metabolites necessary for enhancing ryanodine receptor type 1 (RyR1) activity using [3H]ryanodine ([3H]Ry) binding analysis. The 2,3,6-Cl PCB configuration is most important for optimal recognition by the RyR1 complex and/or critical for sensitizing its activation. Para substitution(s) diminishes the activity with para-chloro having a higher potency than the corresponding para-hydroxy derivative. The addition of a more bulky para-methyl-sulfonyl group eliminates the activity toward RyR1, supporting the importance of the para positions in binding RyR1. The requirement for an intact major T cell immunophilin FKBP12-RyR1 complex was observed with each of 12 active PCB congeners indicating a common mechanism requiring an immunophilin-regulated Ca2+ release channel. An excellent correlation between the relative potencies for doubling [3H]Ry binding and the corresponding initial rates of PCB-induced Ca2+ efflux indicates that [3H]Ry binding analysis provides a measure of dysregulation of microsomal Ca2+ transport. The SAR for activating RyR1 is consistent with those previously reported in several in vivo and in vitro studies, suggesting that a common mechanism may contribute to the toxicity of noncoplanar PCBs. A practical application of the receptor-based screen developed here with RyR1 is that it provides a quantitative SAR that may be useful in predicting biological activity and risk of mixtures containing noncoplanar PCB congeners that have low or a lack of aryl hydrocarbon receptor activity.
authors.affiliation: Department of VM:Molecular Biosciences and Center for Children's Environmental Health, University of California, Davis, California 95616, USA. inpessah@ucdavis.edu
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.forename: Larry G
authors.initials: LG
authors.lastname: Hansen
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Albertson
authors.forename: C Edwin
authors.initials: CE
authors.lastname: Garner
authors.forename: Tram Anh
authors.initials: TA
authors.lastname: Ta
authors.forename: Zung
authors.initials: Z
authors.lastname: Do
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Kim
authors.forename: Patty W
authors.initials: PW
authors.lastname: Wong
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045424:Complex Mixtures / Q000032:analysis; D004785:Environmental Pollutants / Q000032:analysis / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D011078:Polychlorinated Biphenyls / Q000032:analysis / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D018570:Risk Assessment; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D045424:Complex Mixtures; D004785:Environmental Pollutants; D007166:Immunosuppressive Agents; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D011078:Polychlorinated Biphenyls; D022061:Tacrolimus Binding Protein 1A; D002118:Calcium; D020123:Sirolimus