Novel modulators of skeletal muscle FKBP12/calcium channel complex from ianthella basta: Role of FKBP12 in channel gating

Matthew M. Mack, Tadeusz F. Molinski, Edmond D. Buck, Isaac N Pessah

Research output: Contribution to journalArticle

107 Citations (Scopus)

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 μM) 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 μM) Ca2+ 5-fold. Bastadin 5 inhibits Ca2+ uptake into SR vesicles and enhances Ca2+-induced Ca2+ release 8-fold. Bastadin 5 increases single-channel open dwell time, τ1 and τ2, 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 immuno-suppressant 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.

Original languageEnglish (US)
Pages (from-to)23236-23249
Number of pages14
JournalJournal of Biological Chemistry
Volume269
Issue number37
StatePublished - Sep 16 1994

Fingerprint

Tacrolimus Binding Protein 1A
Calcium Channels
Modulators
Ryanodine
Muscle
Skeletal Muscle
Tacrolimus
Adenine Nucleotides
bastadin 5
phosphinothricin
Membranes
Sarcoplasmic Reticulum
Porifera
Caffeine
Biological Products
Isomers
Conformations
Protein Isoforms
Salts

ASJC Scopus subject areas

  • Biochemistry

Cite this

Novel modulators of skeletal muscle FKBP12/calcium channel complex from ianthella basta : Role of FKBP12 in channel gating. / Mack, Matthew M.; Molinski, Tadeusz F.; Buck, Edmond D.; Pessah, Isaac N.

In: Journal of Biological Chemistry, Vol. 269, No. 37, 16.09.1994, p. 23236-23249.

Research output: Contribution to journalArticle

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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 μM) 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 μM) Ca2+ 5-fold. Bastadin 5 inhibits Ca2+ uptake into SR vesicles and enhances Ca2+-induced Ca2+ release 8-fold. Bastadin 5 increases single-channel open dwell time, τ1 and τ2, 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 immuno-suppressant 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.",
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