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Functional implications of modifying RyR-activating peptides for membrane permeability




Dulhunty, Angela
Cengia, Louise
Young, Jaqui
Pace, Suzy M
Lamb, Graham
Harvey, Peta
Chan, Yao-ban
Wimmer, Norbert
Toth, Istvan
Casarotto, Marco

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Nature Publishing Group


Our aim was to determine whether lipoamino acid conjugation of peptides that are high-affinity activators of ryanodine receptor (RyR) channels would (a) render the peptides membrane permeable, (b) alter their structure or (a) reduce their activity. The peptides correspond to the A region of the II-III loop of the skeletal dihydropyridine receptor. The lipoamino acid conjugation increased the apparent permeability of the peptide across the Caco-2 cell monolayer by up to ∼20-fold. Nuclear magnetic resonance showed that the α-helical structure of critical basic residues, required for optimal activation of RyRs, was retained after conjugation. The conjugated peptides were more effective in enhancing resting Ca2+ release, Ca2+-induced Ca2+ release and caffeine-induced Ca2+ release from isolated sarcoplasmic reticulum (SR) than their unconjugated counterparts, and significantly enhanced caffeine-induced Ca2+ release from mechanically skinned extensor digitorum longus (EDL) fibres. The effect of both conjugated and unconjugated peptides on Ca2+ release from skeletal SR was 30-fold greater than their effect on either cardiac Ca2+ release or on the Ca2+ Mg2+ ATPase. A small and very low affinity effect of the peptide in slowing Ca2+ uptake by the Ca2+, Mg2+ ATPase was exacerbated by lipoamino acid conjugation in both isolated SR and in skinned EDL fibres. 7 The results show that lipoamino acid conjugation of A region peptides increases their membrane permeability without impairing their structure or efficacy in activating skeletal and cardiac RyRs.



Keywords: 1,4 dihydropyridine receptor; amino acid; caffeine; lipoamino acid; ryanodine receptor; unclassified drug; alpha helix; article; binding affinity; calcium transport; cell strain CACO 2; conjugation; controlled study; extensor digitorum longus muscle; huma Ca 2+ release; Cardiac muscle; Lipoamino acid conjugation; Ryanodine receptor; Sarcoplasmic reticulum; Skeletal muscle



British Journal of Pharmacology


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