Polypeptides having NMDA receptor activity, nucleic acids encodi

Details Polypeptides having NMDA receptor activity, nucleic acids encodi Polypeptides having NMDA receptor activity, nucleic acids encodi

1995-01-27

1997-07-15

Ulm, John

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Bacteria or actinomycetales; media therefor

435 641, 530350, 536 235, C07K 14705, C12N 510, C12N 1512

Patent

active

056482590

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new polypeptides and to the genetic material permitting their expression. More especially, it relates to new polypeptides having NMDA receptor activity.
Glutamic acid (glutamate) is a so-called excitatory amino acid, whose activity manifests itself in its interaction with specific receptors. Among these receptors, a subtype, designated NMDA (N-methyl-D-aspartate) receptors, appears to be implicated in the central nervous system of mammals, in many processes such as neuronal plasticity, long-term potentiation and also neuronal death or certain degenerative disorders. Pharmacological and molecular biology studies have recently made it possible to demonstrate and clone rat NMDA receptors, the receptor NMDAR1 [Moriyoshi et al., Nature 354 (1991) 31] and the receptor NMDAR2 [Monyer et al., Science 256 (1992) 12], and a mouse NMDA receptor [Yamazaki et al., Febs Lett. 300 (1992) 39].
The present invention is the outcome of the demonstration of new polypeptides having NMDA receptor activity. While belonging to the family of receptors associated with ion channels, these new polypeptides differ from the NMDA receptors already described from both a structural standpoint and a pharmacological standpoint. In particular, the receptors in question are of presynaptic origin, involved, in particular, in long-term potentiation (LTP).
More especially, the invention is the outcome of the isolation and characterization of new polypeptides, designated GR33, and also of the genetic material permitting their expression or identification. The invention also lies in the preparation of probes and of recombinant cells enabling the GR33 polypeptides to be exploited in diagnosis and the development of new active molecules.
A first subject of the invention hence lies in polypeptides comprising all or part of the peptide sequence SEQ ID No. 2 or of a derivative of the latter.
For the purposes of the present invention, the term derived denotes any molecule obtained by modification, of a genetic and/or chemical nature, of the peptide sequence SEQ ID No. 2. Modification of a genetic and/or chemical nature is understood to mean any mutation, substitution, deletion, addition and/or modification of one or more residues. Such derivatives may be generated for different purposes, such as, in particular, that of increasing the affinity of the peptide for its ligand(s), that of improving its levels of production, that of increasing its resistance to proteases, that of increasing and/or modifying its activity or that of endowing it with new pharmacokinetic and/or biological properties. Among derivatives resulting from an addition, chimeric polypeptides containing an additional heterologous portion attached at one end may, for example, be mentioned. The term derivative also comprises polypeptides homologous with the polypeptide SEQ ID No. 2, originating from other cell sources, and in particular from cells of human origin or of other organisms and possessing an activity of the same type. Such homologous polypeptides may be obtained by hybridization and/or PCR experiments, as described in the examples.
Preferably, the polypeptides of the invention are polypeptides possessing the capacity to bind glutamate. Still more preferably, they are polypeptides having NMDA receptor activity. Still according to a preferred embodiment, the polypeptides of the invention are capable of being recognized by antibodies which recognize the complete peptide sequence SEQ ID No. 2.
A particular embodiment of the invention is represented by the polypeptide GR33 comprising the whole peptide sequence SEQ ID No. 2. As shown in the examples, this polypeptide may be expressed in Xenopus eggs to form a functional glutamate receptor displaying all the pharmacological characteristics of an NMDA receptor: completely; antagonists such as AP5 (D-2-amino-5-phosphonovaleric acid) or AP7 (D-2-amino-7-phosphonoheptanoic acid); approximately 10 .mu.M, corresponding to the values determined in the cases of the receptor NMDAR1; quisqualate, homocysteate), gl

REFERENCES:
Inoue et al., J. of Biol. Chem. 267(15):10613-10618, 25 May 1992.
J. Biol. Chem. 267(15): 10613-19, May 25, 1992 Cloning and sequence analysis of cDNA for a neuronal cell membrane antigen, HPC-1'.

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