Methods for modulating neuronal responses
OwnerYu Wang, Yushan Wang +3inventors
InventorsYu Wang, Yushan Wang, Anthony Phillips, Lidong Liu, Yitao Liu
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Abstract
The invention provides, in part, methods and reagents for modulating neuronal apoptosis and for modulating synaptic plasticity.
Claims47
1-48. (canceled)
A method of modulating NMDA-mediated neuronal apoptosis, the method comprising contacting a neuronal cell with an inhibitor of AMPA receptor endocytosis.
A method of modulating AMPA receptor endocytosis, the method comprising contacting a cell expressing an AMPA receptor with a modulatory compound comprising the amino acid sequence set forth in Table I or conservative substitutions thereof, Formula I, or Formula A, or homologous sequences thereto found in the C-terminus of the GluR2, GluR3, or GluR4 subunits of the AMPA receptor or a fragment or variant thereof, or comprising an antibody that specifically binds the amino acid sequence set forth in Table I or conservative substitutions thereof, Formula I, or Formula A, or homologous sequences thereto found in the C-terminus of the GluR2, GluR3, or GluR4 subunits of the AMPA receptor.
A method of treating or preventing neurological damage or dysfunction in a subject, the method comprising administering an effective amount of an inhibitor of AMPA receptor endocytosis to the subject.
The method of any one of claims 12 through 16, wherein the inhibitor further comprises the amino acid sequence YGRKKRRQRRR or a carrier peptide sequence that facilitates translocation of the inhibitor across cell membranes.
A method of modulating synaptic plasticity in a subject, the method comprising administering an effective amount of an inhibitor of AMPA receptor endocytosis to the subject.
A method of screening for a modulator of AMPA receptor endocytosis, the method comprising:
- (a) providing a system comprising
- (i) an AMPA receptor polypeptide or a biologically-active fragment thereof;
- (ii) an inhibitor of AMPA receptor endocytosis;
- (b) providing a test compound;
- (c) contacting the system with the test compound;
- and
- (d) determining whether the test compound modulates AMPA receptor endocytosis.
A method of screening for a modulator of AMPA receptor endocytosis, the method comprising:
- (a) providing an AMPA receptor polypeptide or a biologically-active fragment thereof;
- (b) providing a test compound;
- (c) contacting the AMPA receptor polypeptide or a biologically-active fragment thereof with the test compound;
- and
- (d) determining whether the test compound modulates AMPA receptor endocytosis.
A polypeptide comprising an amino acid sequence substantially identical to at least one of the sequences selected from the group consisting of YREGYNVYGIE, YKEGYNVYGIE, YREGYNVYG, and YKEGYNVYG.
A polypeptide comprising an amino acid sequence substantially identical to at least one of the sequences set forth in Table I.
A substantially pure compound comprising of Formula I:
- Z1-X1-X2-E-G-X3-N-V-X4-G-Z2;
- (I)
- wherein
- X1 is Y, D, E, S, or T;
- X2 is K or R;
- X3 is Y, D, E, S, or T;
- X4 is Y, D, E, S, or T;
- Z, is H2N—, RHN— or, RRN—;
- Z2 is —C(O)OH, —C(O)R, —C(O)OR, —C(O)NHR, —C(O)NRR;
- R at each occurrence is independently selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, substituted (C1-C6) alkyl, substituted (C1-C6) alkenyl, or substituted (C1-C6) alkynyl;
- wherein “—” is a covalent linkage, and wherein the compound is an inhibitor of AMPA receptor endocytosis.
A method of modulating NMDA-mediated neuronal apoptosis, the method comprising contacting a neuronal cell with an inhibitor of clathrin-mediated endocytosis.
Dependencies are inferred from the claim text.