title: Green tea catechins are potent sensitizers of ryanodine receptor type 1 (RyR1).
abstract: Catechins, polyphenols extracted from green tea leaves, have a broad range of biological activities although the specific molecular mechanisms responsible are not known. At the high experimental concentrations typically used polyphenols bind to membrane phospholipid and also are easily auto-oxidized to generate superoxide anion and semiquinones, and can adduct to protein thiols. We report that the type 1 ryanodine receptor (RyR1) is a molecular target that responds to nanomolar (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG). Single channel analyses demonstrate EGCG (5-10nM) increases channel open probability (Po) twofold, by lengthening open dwell time. The degree of channel activation is concentration-dependent and is rapidly and fully reversible. Four related catechins, EGCG, ECG, EGC ((-)-epigallocatechin) and EC ((-)-epicatechin) showed a rank order of activity toward RyR1 (EGCG>ECG>>EGC>>>EC). EGCG and ECG enhance the sensitivity of RyR1 to activation by < or =100microM cytoplasmic Ca(2+) without altering inhibitory potency by >100microM Ca(2+). EGCG as high as 10microM in the extracellular medium potentiated Ca(2+) transient amplitudes evoked by electrical stimuli applied to intact myotubes and adult FDB fibers, without eliciting spontaneous Ca(2+) release or slowing Ca(2+) transient recovery. The results identify RyR1 as a sensitive target for the major tea catechins EGCG and ECG, and this interaction is likely to contribute to their observed biological activities.
authors.affiliation: Department of Molecular Biosciences, University of California, Davis, 95616, United States of America. fengwei@ucdavis.edu
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Gennady
authors.initials: G
authors.lastname: Cherednichenko
authors.forename: Chris W
authors.initials: CW
authors.lastname: Ward
authors.forename: Isela T
authors.initials: IT
authors.lastname: Padilla
authors.forename: Elaine
authors.initials: E
authors.lastname: Cabrales
authors.forename: José R
authors.initials: JR
authors.lastname: Lopez
authors.forename: José M
authors.initials: JM
authors.lastname: Eltit
authors.forename: Paul D
authors.initials: PD
authors.lastname: Allen
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: D000200:Action Potentials; D000328:Adult; D016588:Anticarcinogenic Agents; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010936:Plant Extracts / Q000737:chemistry*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects; D013662:Tea / Q000737:chemistry
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; D010936:Plant Extracts; D019837:Ryanodine Receptor Calcium Release Channel; D013662:Tea; D002392:Catechin; C062669:epicatechin gallate; C045651:epigallocatechin gallate; C057580:gallocatechol
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