Title : Engineering of alpha-conotoxin MII-derived peptides with increased selectivity for native alpha6beta2* nicotinic acetylcholine receptors - Pucci_2011_FASEB.J_25_3775 |
Author(s) : Pucci L , Grazioso G , Dallanoce C , Rizzi L , De Micheli C , Clementi F , Bertrand S , Bertrand D , Longhi R , De Amici M , Gotti C |
Ref : FASEB Journal , 25 :3775 , 2011 |
Abstract :
alpha6beta2* 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. alpha6beta2* 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 alpha6beta2* 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 alpha6beta2* receptors but not for the very similar alpha3beta2* subtype. As docking studies also suggested that E11 of MII might be a key residue engendering alpha6beta2* vs. alpha3beta2* selectivity, we prepared MII[E11R] and RDP-MII[E11R] peptides. Their affinity and potency for native alpha6beta2* receptors were similar to those of their parent analogues, whereas, for the oocyte expressed rat alpha3beta2* 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 alpha6beta2* vs. alpha3beta2* selectivity in vivo. |
PubMedSearch : Pucci_2011_FASEB.J_25_3775 |
PubMedID: 21778325 |
Pucci L, Grazioso G, Dallanoce C, Rizzi L, De Micheli C, Clementi F, Bertrand S, Bertrand D, Longhi R, De Amici M, Gotti C (2011)
Engineering of alpha-conotoxin MII-derived peptides with increased selectivity for native alpha6beta2* nicotinic acetylcholine receptors
FASEB Journal
25 :3775
Pucci L, Grazioso G, Dallanoce C, Rizzi L, De Micheli C, Clementi F, Bertrand S, Bertrand D, Longhi R, De Amici M, Gotti C (2011)
FASEB Journal
25 :3775