STRUCTURE-FUNCTION RELATIONSHIPS OF THE CCK-B RECEPTOR

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The cholecystokinin (CCK) type B receptor in brain plays an important role in modulating anxiety and panic attacks. CCK-B receptor antagonists have been shown to block the neuronal response to CCK and have been proposed as a potentially efficacious new class of anti-anxiety medication. Isolation of a cloned CCK-B receptor and expression in a heterologous cell line, would expedite the development of this new class of drugs. We have isolated a cDNA encoding the first cloned member of the gastrin/CCK receptor family and have evidence that our receptor is highly homologous to the brain CCK-B receptor. Understanding the link between structure and function of the CCK-B receptor will allow more rational design of receptor antagonists. Determination of whether the "CCK-B receptor" (like the biogenic amine receptors) represents a family of related receptors, each with characteristic pharmacology, rather than a single receptor, would allow development of drugs targeted to a specific receptor subtype in brain. We have brought together a consortium of individuals with expertise in molecular biology, pharmacology, protein chemistry, and receptor characterization to undertake the isolation, expression, and characterization of the CCK-B and other related brain receptors. Collectively this group is experienced in all aspects of the proposed project and have been working together for the past year on the cloning and characterization of the gastrin receptor (PNAS, 1992, in press). The first objective is to isolate the CCK-B and related receptors from brain by low stringency hybridization and PCR with degenerate oligonucleotides. The CCK-B and related receptors will ten be pharmacologically characterized to determine ligand binding specificity and the second messenger pathways which couple to these receptors. The ligand binding sites will be mapped with photoaffinity labels which we have previously used in characterizing other members of this receptor family as well as with a series of new intrinsic photoaffinity probes which we will develop specifically for the CCK-B receptor.