Molecular Biological Studies on the Diversity of Chemical Signalling in Tachykinin Peptidergic Neurons" zy JAMES E. KRAUSE, ANDREW D. HERSHEY, PHILIP E. DYKEMA, AND YASUO TAKEDA zyxw Department of Anatomy and Neurobiology Washington University School of Medicine 660 South Euclid Avenue St. Louis, Missouri 63110 INTRODUCTION The recent advances in peptide and protein biochemistry, and especially in molecular biology, have allowed molecular neurobiologists the opportunity to understand the phys- ical basis of cell-cell communication in the nervous system. Within the past twenty years, it has been generally recognized that peptide-secreting neurons comprise a significant portion of the communicative neurons involved in chemical neurotransmission throughout the neuraxis. With regard to peptide-secreting and peptide-receptive neuronal systems, the technical advances have resulted in many applications toward the understanding of I zy ) the specific ligands involved in cell-cell communication, zyxwv 2) the physiological receptors with which the ligands interact, and 3) how the processes of ligand production and receptor recognition and activation are regulated at both cellular and molecular levels. Our interest for the past several years has been focused upon neurons that secrete the class of peptide neurotransmitters called tachykinins, and the cells that respond to the tachykinin peptides. The tachykinins represent a family of neuropeptides so named be- cause of their ability to rapidly stimulate the contraction of gut tissue, though by no means does this represent their sole biological activity. Peptides that belong to this family are distributed differentially throughout the nervous system, as are the receptors with which they interact. In this article we use the tachykinin peptide neurotransmitter system to illustrate how some uses of recently developed molecular biological techniques and strat- egies, coupled with the use of peptide and protein biochemical methods, have resulted in a greater appreciation of the diversity of chemical signalling within these peptide- secreting neurons. Preprotachykinin Genes That Encode the Multiple Tachykinin Peptides The mammalian tachykinin peptides isolated to date include Substance P (SP), Neu- rokinin A (NKA), Neuropeptide K (NPK), Neuropeptide y (NP,), and Neurokinin B (NKB).'.' Their primary structures are shown in FIGURE 1. zyx As a result of cDNA and genomic cloning experiment^,^.^ it is now established that SP, NKA, NPK, and NPy are derived from the first preprotachykinin (PPT) gene isolated (called the PPT I or PPT A "This work was supported in part by National Institutes of Health Grant NS21937 and a grant from the Pew Memorial Trust. JEK is a Pew Scholar in the Biomedical Sciences. 254