title: Novel modulators of skeletal muscle FKBP12/calcium channel complex from Ianthella basta. Role of FKBP12 in channel gating.
abstract: Macrocyclic natural products derived from bromotyrosine isolated from the sponge Ianthella basta are shown to selectively modulate the skeletal isoform of the ryanodine-sensitive sarcoplasmic reticulum calcium channel by a novel mechanism involving the FKBP12/RyR-1 complex. Bastadins 5, 7, and the newly identified isomer of bastadin 5, bastadin 19, show marked differences in potency and efficacy toward activation of the binding of [3H]ryanodine. In physiological salt, bastadin 5 (5 microM) increases the [3H]ryanodine binding capacity of SR membranes 5-fold, by stabilizing the high affinity conformation of RyR-1 for ryanodine without shifting the affinity of the activator site for Ca2+ or altering the response to caffeine or adenine nucleotides. Bastadin 5 decreases the inhibitory potency of Mg2+ 8-fold and high (> 100 microM) Ca2+ 5-fold. Bastadin 5 inhibits Ca2+ uptake into SR vesicles and enhances Ca(2+)-induced Ca2+ release 8-fold. Bastadin 5 increases single-channel open dwell time, tau 1 and tau 2, 65- and 92-fold, respectively, without changing unitary conductance for Cs+ (450 picosiemans) or open probability. Most significant is the finding that the unique actions of bastadin 5 on [3H]ryanodine binding and Ca2+ transport are antagonized by the immunosuppressant FK506. FK506 alone weakly enhances the binding of [3H]ryanodine, compared to bastadin 5. However, FK506 diminishes bastadin 5-induced changes in [3H]ryanodine binding and Ca2+ transport without altering the efficacy of adenine nucleotides. Unlike FK506, bastadin 5 does not directly promote the dissociation of FKBP12 from the RyR-1 membrane complex; however, it markedly enhances the release of FKBP12 induced by FK506. These results suggest that the bastadin 5 effector site is a novel modulatory domain on FKBP12. Bastadins represent a new class of compounds to gain insight into the functional interactions between FKBP12 and RyR-1.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis 95616.
authors.forename: M M
authors.initials: MM
authors.lastname: Mack
authors.forename: T F
authors.initials: TF
authors.lastname: Molinski
authors.forename: E D
authors.initials: ED
authors.lastname: Buck
authors.forename: I N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000502:physiology*; D015394:Molecular Structure; D009124:Muscle Proteins / Q000187:drug effects* / Q000502:physiology; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism; D010647:Phenyl Ethers / Q000494:pharmacology*; D011161:Porifera; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000187:drug effects; D022021:Tacrolimus Binding Proteins
chemical_list: D015220:Calcium Channels; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D009124:Muscle Proteins; D010647:Phenyl Ethers; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D022021:Tacrolimus Binding Proteins