Functional implications of modifying RyR-activating peptides for membrane permeability
| Autor: | Norbert Wimmer, Angela F. Dulhunty, Yiu-Ngok Chan, Louise Cengia, Jacqui Young, Graham D. Lamb, Peta J. Harvey, Suzy M. Pace, Istvan Toth, Marco G. Casarotto |
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| Rok vydání: | 2005 |
| Předmět: |
Pharmacology
chemistry.chemical_classification biology Membrane permeability Ryanodine receptor Chemistry ATPase Endoplasmic reticulum Cardiac muscle chemistry.chemical_element Peptide Calcium musculoskeletal system Amino acid medicine.anatomical_structure Biochemistry biology.protein Biophysics medicine |
| Zdroj: | British Journal of Pharmacology. 144:743-754 |
| ISSN: | 0007-1188 |
| Popis: | 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 B20-fold. 3 Nuclear magnetic resonance showed that the a-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 Ca 2 þ release, Ca 2 þ -induced Ca 2 þ release and caffeine-induced Ca 2 þ release from isolated sarcoplasmic reticulum (SR) than their unconjugated counterparts, and significantly enhanced caffeine-induced Ca 2 þ release from mechanically skinned extensor digitorum longus (EDL) fibres. 5 The effect of both conjugated and unconjugated peptides on Ca 2 þ release from skeletal SR was 30-fold greater than their effect on either cardiac Ca 2 þ release or on the Ca 2 þ Mg 2 þ ATPase. 6 A small and very low affinity effect of the peptide in slowing Ca 2 þ uptake by the Ca 2 þ ,M g 2 þ 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. |
| Databáze: | OpenAIRE |
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