Tachykinin Receptors: A Radioligand Binding Perspective

Abstract

The last decade has witnessed major breakthroughs in the study of tachykinin receptors. The currently described NK-1, NK-2, and NK-3 receptors have been sequenced and cloned from various mammalian sources. A far greater variety of tachykinin analogues are now available for use as selective agonists and antagonists. Importantly, potent nonpeptide antagonists highly selective for the NK-1 and NK-2 receptors have been developed recently. These improved tools for tachykinin receptor characterization have enabled us to describe at least three distinct receptor types. Furthermore, novel antagonists have yielded radioligand binding and functional data strongly favoring the existence of putative subtypes of NK-1 and especially NK-2 receptors. Whether these subtypes are species variants or true within-species subtypes awaits further evidence. As yet undiscovered mammalian tachykinins, or bioactive fragments, may have superior potency at a specific receptor class. The common C terminus of tachykinins permits varying degrees of interaction at essentially all tachykinin receptors. Although the exact physiological significance of this inherent capacity for receptor "cross talk" remains unknown, one implication is for multiple endogenous ligands at a single receptor. For example, NP gamma and NPK appear to be the preferred agonists and binding competitors at some NK-2 receptors, previously thought of as exclusively "NKA-preferring." Current evidence suggests that tachykinin coexistence and expression of multiple receptors may also occur with postulated NK-2 and NK-1 receptor subtypes. Other "tachykinin" receptors may recognize preprotachykinins and the N terminus of SP. In light of these recent developments, the convenient working hypothesis of three endogenous ligands (SP, NKA, and NKB) for three basic receptor types (NK-1, NK-2, and NK-3) may be too simplistic and in need of amendment as future developments occur (Burcher et al., 1991b). In retrospect, the 1980s contributed greatly to our understanding of the structure, function, and regulation of tachykinins and their various receptors. The development of improved, receptor subtype-selective antagonists and radioligands, in addition to recent advances in molecular biological techniques, may lead to a more conclusive pharmacological and biochemical characterization of tachykinin receptors. The 1990s may prove to be the decade of application, where a better understanding of the roles played by endogenous tachykinins (at various receptor subtypes) under pathophysiological conditions will no doubt hasten the realization of clinically useful therapeutic agents.