Skip navigation
Skip navigation

Activation and Inhibition of Skeletal RyR Channels by a Part of the Skeletal DHPR II-III Loop: Effects of DHPR Ser 687 and FKBP12

Dulhunty, Angela; Laver, Derek Rowland; Gallant, Esther; Casarotto, Marco; Pace, Suzy M; Curtis, Suzanne

Description

Peptides, corresponding to sequences in the N-terminal region of the skeletal muscle dihydropyridine receptor (DHPR) II-III loop, have been tested on sarcoplasmic reticulum (SR) Ca2+ release and ryanodine receptor (RyR) activity. The peptides were: A1, Thr671-Leu690; A2, Thr671-Leu690 with Ser687 Ala substitution; NB, Gly689-Lys708 and A1S, scrambled A1 sequence. The relative rates of peptide-induced Ca2+ release from normal (FKBP12+) SR were A2 > A1 > A1S > NB. Removal of FKBP12 reduced the...[Show more]

dc.contributor.authorDulhunty, Angela
dc.contributor.authorLaver, Derek Rowland
dc.contributor.authorGallant, Esther
dc.contributor.authorCasarotto, Marco
dc.contributor.authorPace, Suzy M
dc.contributor.authorCurtis, Suzanne
dc.date.accessioned2015-12-13T23:24:55Z
dc.identifier.issn0006-3495
dc.identifier.urihttp://hdl.handle.net/1885/92448
dc.description.abstractPeptides, corresponding to sequences in the N-terminal region of the skeletal muscle dihydropyridine receptor (DHPR) II-III loop, have been tested on sarcoplasmic reticulum (SR) Ca2+ release and ryanodine receptor (RyR) activity. The peptides were: A1, Thr671-Leu690; A2, Thr671-Leu690 with Ser687 Ala substitution; NB, Gly689-Lys708 and A1S, scrambled A1 sequence. The relative rates of peptide-induced Ca2+ release from normal (FKBP12+) SR were A2 > A1 > A1S > NB. Removal of FKBP12 reduced the rate of A1-induced Ca2+ release by ~30%. A1 and A2 (but not NB or A1S), in the cytoplasmic (cis) solution, either activated or inhibited single FKBP12 + RyRs. Maximum activation was seen at -40 mV, with 10 μM A1 or 50 nM A2. The greatest A1-induced increase in mean current (sixfold) was seen with 100 nM cis Ca2+. Inhibition by A1 was greatest at +40 mV (or when permeant ions flowed from cytoplasm to SR lumen) with 100 μM cis Ca2+, where channel activity was almost fully inhibited. A1 did not activate FKBP12-stripped RyRs, although peptide-induced inhibition remained. The results show that peptide A activation of RyRs does not require DHPR Ser687, but required FKBP12 binding to RyRs. Peptide A must interact with different sites to activate or inhibit RyRs, because current direction-, voltage-, cis [Ca2+]- , and FKBP12-dependence of activation and inhibition differ.
dc.publisherBiophysical Society
dc.sourceBiophysical Journal
dc.subjectKeywords: 1,4 dihydropyridine receptor; alanine; binding protein; calcium; glycine; leucine; lysine; peptide; receptor; ryanodine receptor; serine; tacrolimus; threonine; unclassified drug; amino acid analysis; amino acid composition; amino acid sequence; amino aci
dc.titleActivation and Inhibition of Skeletal RyR Channels by a Part of the Skeletal DHPR II-III Loop: Effects of DHPR Ser 687 and FKBP12
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume77
dc.date.issued1999
local.identifier.absfor060199 - Biochemistry and Cell Biology not elsewhere classified
local.identifier.ariespublicationMigratedxPub23558
local.type.statusPublished Version
local.contributor.affiliationDulhunty, Angela, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLaver, Derek Rowland, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationGallant, Esther, University of Minnesota
local.contributor.affiliationCasarotto, Marco, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationPace, Suzy M, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationCurtis, Suzanne, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.startpage189
local.bibliographicCitation.lastpage203
dc.date.updated2015-12-12T09:22:33Z
local.identifier.scopusID2-s2.0-0032975217
CollectionsANU Research Publications

Download

File Description SizeFormat Image
01_Dulhunty_Activation_and_Inhibition_of_1999.pdf277.81 kBAdobe PDF    Request a copy


Items in Open Research are protected by copyright, with all rights reserved, unless otherwise indicated.

Updated:  17 November 2022/ Responsible Officer:  University Librarian/ Page Contact:  Library Systems & Web Coordinator