Imgenex Corp. develops and commercializes novel reagents for the scientific study of human biology and disease and for the production of new diagnostic assays and potential therapies of such diseases. These novel reagents include antibodies, gene and protein expression systems, and arrays of various cells and tissues for use in studies of functional genomics. Areas of biological interest at IMGENEX include cancer, apoptosis (programmed cell death), molecular signaling pathways, cellular aging, and metabolic and infectious diseases.

GABA, gamma-amino butyric acid, is an important amino acid-based signaling molecule in basic neuronal pathways, and acts as the major inhibitory neurotransmitter in the central nervous system. Alterations in it's functional delivery have been implicated in a variety of neurodegenerative disorders, including epilepsy, Parkinson's disease, and Huntington's disease (1). Antibodies against GABA receptors are important tools to characterize GABA signaling pathway.

Five types of molecules control GABA signaling: proteins responsible for its synthesis, packaging, binding, re-uptake, and degradation. GABA synthesis tales place through the decarboxylation of glutamate by glutamic decarboxylase (GAD). Thus far two different, functional forms of GAD have been isolated GAD65 and GAD67 (2,3). GABA is packaged into vesicles by the vesicular GABA transporter (vGAT). Only one vGAT gene has been cloned (4).

GABA is removed from the extracellular space by plasma membrane GABA transporters (GATs). Four different cloned GATs have been isolated (7). The final type of GABA-controlling protein is the GABA-degrading enzyme, GABA-transminase (GABA-T). Thus far, only one gene for GABA-T has been cloned (8).

All five of these molecules may be good drug therapy targets, but both the synthesis enzymes and the GABA receptors are particularly attractive, due to the potential for increased synthesis or signal transduction with modification pf the proteins or through interaction with bio-functional antibodies.

Reference:

1. Kleppner S and Tobin A. GABA signaling: therapeutic targets for epilepsy, Parkinson's disease and Huntington's disease. Emerging Ther Targets, 5: 219-239 (2001).

2. Kaufman DI, Houser CR, and Tobin A. Two forms of the gamma-aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J Neurochem, 56: 720-723 (1991).

3. Erlander MG, Tillakarante N, Feldblum S, Patel N, and Tobin A. Two distinct genes encode distinct glutamate decarboxylases. Neuron, 7, 91-100 (1991).

4. McIntire SI, Reimer R, Schuske K, Edwards RH, and Jorgensen EM. Identification and characterization of the vesicular GABA transporter. Nature, 389: 870-876 (1997).

5. Whiting P. The GABAA receptor gene family: new targets for therapeutic intervention. Neurochem. Int., 34: 387-390 (1999).

6. Jones KA, Borowsky B, Tamm JA, eat al. GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature, 396: 674-679 (1998).

7. Worrall DM and Williams DC. Sodium ion-dependent transporters for neurotrasmitters: a review of recent developments. Biochem. J., 297: 425-436 (1994).

8. Medina-Kauwe L, Tillkarante N, Wu J, and Tobin A. A rat brain cDNA encodes enzymatically active GABA transaminase and provides a molecular probe for GABA-catabolizing cells. J. Neurochem., 62: 1267-1275 (1994),