Functional implications of modifying RyR‐activating peptides for membrane permeability

Dulhunty, Angela F., Cengia, Louise, Young, Jacqui, Pace, Suzy M., Harvey, Peta J., Lamb, Graham D., Chan, Yiu-Ngok, Wimmer, Norbert, Toth, Istvan and Casarotto, Marco G. (2005) Functional implications of modifying RyR‐activating peptides for membrane permeability. British Journal of Pharmacology, 144 6: 743-754. doi:10.1038/sj.bjp.0705981

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Author Dulhunty, Angela F.
Cengia, Louise
Young, Jacqui
Pace, Suzy M.
Harvey, Peta J.
Lamb, Graham D.
Chan, Yiu-Ngok
Wimmer, Norbert
Toth, Istvan
Casarotto, Marco G.
Title Functional implications of modifying RyR‐activating peptides for membrane permeability
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
Publication date 2005-03-01
Sub-type Article (original research)
DOI 10.1038/sj.bjp.0705981
Open Access Status File (Author Post-print)
Volume 144
Issue 6
Start page 743
End page 754
Total pages 12
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject C1
320501 Pharmaceutical Sciences and Pharmacy
730106 Cardiovascular system and diseases
Formatted abstract
1. 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.

2. The lipoamino acid conjugation increased the apparent permeability of the peptide across the Caco-2 cell monolayer by up to ∼20-fold.

3. Nuclear magnetic resonance showed that the α-helical structure of critical basic residues, required for optimal activation of RyRs, was retained after conjugation.

4. 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.

5. 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.

6. 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.
© 2005 Nature Publishing Group
Keyword Pharmacology & Pharmacy
Lipoamino Acid Conjugation
Ryanodine Receptor
Sarcoplasmic Reticulum
Skeletal Muscle
Cardiac Muscle
Ca2+ Release
Skeletal-muscle Fibers
Dihydropyridine Receptor
Ryanodine Receptors
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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Created: Wed, 15 Aug 2007, 16:19:32 EST