alpha 6 beta 2* Nicotinic acetylcholine receptors are expressed in selected central nervous system areas, where they are involved in striatal dopamine (DA) release and its behavioral consequences, and other still uncharacterized brain activities. alpha 6 beta 2* receptors are selectively blocked by the alpha-conotoxins MII and PIA, which bear a characteristic N-terminal amino acid tail [arginine (R), aspartic acid (D), and proline (P)]. We synthesized a group of PIA-related peptides in which R1 was mutated or the RDP motif gradually removed. Binding and striatal DA release assays of native rat alpha 6 beta 2* receptors showed that the RDP sequence, and particularly residue R1, is essential for the activity of PIA. On the basis of molecular modeling analyses, we synthesized a hybrid peptide (RDP-MII) that had increased potency (7-fold) and affinity (13-fold) for alpha 6 beta 2* receptors but not for the very similar alpha 3 beta 2* subtype. As docking studies also suggested that E11 of MII might be a key residue engendering alpha 6 beta 2* vs. alpha 3 beta 2* selectivity, we prepared MII[E11R] and RDP-MII[E11R] peptides. Their affinity and potency for native alpha 6 beta 2* receptors were similar to those of their parent analogues, whereas, for the oocyte expressed rat alpha 3 beta 2* subtype, they showed a 31- and 14-fold lower affinity and 21- and 3.5-fold lower potency. Thus, MII[E11R] and RDP-MII[E11R] are potent antagonists showing a degree of alpha 6 beta 2* vs. alpha 3 beta 2* selectivity in vivo.-Pucci, L., Grazioso, G., Dallanoce, C., Rizzi, L., De Micheli, C., Clementi, F., Bertrand, S., Bertrand, D., Longhi, R., De Amici, M., Gotti, C. Engineering of alpha-conotoxin MII-derived peptides with increased selectivity for native alpha 6 beta 2* nicotinic acetylcholine receptors. FASEB J. 25, 3775-3789 (2011). www.fasebj.org
Engineering of alpha-conotoxin MII-derived peptides with increased selectivity for native alpha 6 beta 2*nicotinic acetylcholine receptors
Clementi Francesco;Gotti Cecilia
2011
Abstract
alpha 6 beta 2* Nicotinic acetylcholine receptors are expressed in selected central nervous system areas, where they are involved in striatal dopamine (DA) release and its behavioral consequences, and other still uncharacterized brain activities. alpha 6 beta 2* receptors are selectively blocked by the alpha-conotoxins MII and PIA, which bear a characteristic N-terminal amino acid tail [arginine (R), aspartic acid (D), and proline (P)]. We synthesized a group of PIA-related peptides in which R1 was mutated or the RDP motif gradually removed. Binding and striatal DA release assays of native rat alpha 6 beta 2* receptors showed that the RDP sequence, and particularly residue R1, is essential for the activity of PIA. On the basis of molecular modeling analyses, we synthesized a hybrid peptide (RDP-MII) that had increased potency (7-fold) and affinity (13-fold) for alpha 6 beta 2* receptors but not for the very similar alpha 3 beta 2* subtype. As docking studies also suggested that E11 of MII might be a key residue engendering alpha 6 beta 2* vs. alpha 3 beta 2* selectivity, we prepared MII[E11R] and RDP-MII[E11R] peptides. Their affinity and potency for native alpha 6 beta 2* receptors were similar to those of their parent analogues, whereas, for the oocyte expressed rat alpha 3 beta 2* subtype, they showed a 31- and 14-fold lower affinity and 21- and 3.5-fold lower potency. Thus, MII[E11R] and RDP-MII[E11R] are potent antagonists showing a degree of alpha 6 beta 2* vs. alpha 3 beta 2* selectivity in vivo.-Pucci, L., Grazioso, G., Dallanoce, C., Rizzi, L., De Micheli, C., Clementi, F., Bertrand, S., Bertrand, D., Longhi, R., De Amici, M., Gotti, C. Engineering of alpha-conotoxin MII-derived peptides with increased selectivity for native alpha 6 beta 2* nicotinic acetylcholine receptors. FASEB J. 25, 3775-3789 (2011). www.fasebj.orgI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
