ABSTRACT
Crystallography, mutational mapping and crosslinking are but a few of the experimental techniques that have helped to elucidate the underlying principles of molecular recognition between macromolecules and to improve our understanding of the evolution of the structure-activity relationship (SAR). While this development has been particularly successful for small and rigid ligands and substrates that bind to larger hydrophilic biomolecules, our understanding of membrane-embedded proteins is still rather limited. This review uses the example of the neuropeptide family of tachykinins and their G-protein coupled receptors (GPCR) to present how complementary experimental strategies over the past decades have nourished and modified conceptual models of the structural requisites of molecular recognition and function. Given the little we know, the pertinent question is how we proceed from here.
Subject(s)
Tachykinins/history , Animals , History, 20th Century , History, 21st Century , Humans , Protein Conformation , Receptors, Tachykinin/chemistry , Receptors, Tachykinin/history , Structure-Activity Relationship , Tachykinins/chemistryABSTRACT
This article highlights major findings from physiological and pharmacological studies conducted in the pre- and post-genomic era examining the roles of substance P (SP) and other tachykinins in the response of the carotid body to hypoxia, in the ventilatory response to hypoxia and in respiratory rhythm generation. In the post-genomic period, the hypoxic ventilatory responses of mice carrying targeted deletion of genes that affect synthesis or degradation or receptor interaction of SP have been examined by us and also by other investigators. A brief summary of the findings from these investigations will also be presented. The combined observations from the pre- and post-genomic era strongly support the involvement of SP and also other tachykinins in the control of respiration during hypoxia.
