Overview of the Primary Structure, Tissue-Distribution, and Functions of Tachykinins and their Receptors

Abstract

Tachykinins (TKs) constitute the largest vertebrate brain/gut peptide family. Since discovery of Substance P as a structurally unidentified vasodilatory and contractile compound in 1931, continuous and tremendous advances have been made regarding molecular and functional characterization of TKs and their receptors, revealing diverse molecular species of TK peptides with a C-terminal consensus -Phe-X-Gly-Leu-Met-NH2, not ubiquitous but wide distribution and multiple biological activities of TKs and their receptors in central and peripheral tissues, elaborate and complicated ligand-recognition and multiple functional conformation of receptors, evolutionary aspects of brain/gut peptides, and the implication of TK peptides and receptors in many disorders of current keen interest. Indeed, the tachykinergic systems are now regarded as promising targets of novel clinical agents aimed at a variety of pathological symptoms and processes such as nociception, inflammation, neurodegeneration, and neuroprotection. In this review, we present an overview of basic knowledge and a buildup of recent advances in extensive fields of the 'tachykinin kingdom' including mammalian non-neuronal TKs, invertebrate salivary gland-specific TKs and TK-related brain/gut peptides (TKRPs). These findings shed new light on (1) the biological and biochemical significance of TKs, (2) evolutionary relationship of the structures and functions between mammalian and non-mammalian TK family peptides and receptors, and (3) the binding mode for the TK family peptides and their receptors and the resultant activation of the complexes that are essential for design and development of leading compounds.

Modulation of lymphatic muscle contractility by the neuropeptide substance P

“…These actions of SP on lymphatic muscle would act in concert with its effects on permeability to promote fluid filtration from exchange vessels (18,25), stimulating lymphatic pump activity through enhanced lymphatic filling pressure. Because SP release from numerous cell types is associated with various inflammatory conditions (27,41,45,52), its stimulatory actions, at low concentrations, on the lymphatic pump may play an important role in the homeostatic control of interstitial fluid balance in both normal and inflammatory states.…”

“…neurokinin; edema; inflammation; lymphatic pump; inotropy; chronotropy; thromboxane A2 SUBSTANCE P (SP) is an 11-amino acid neuropeptide (36) often associated with cells of lymphoid tissue (15,19,21,22,46,47). SP is released from enteric nerves, sensory nerves, and inflammatory cells (27,41,45,52). Correspondingly, SP receptors are expressed on endothelium and muscle of blood and lymphatic vessels, on nerves innervating those vessels, and on associated immune and inflammatory cells (31,36,44).…”

“…SP is released from enteric nerves, sensory nerves, and inflammatory cells (27,41,45,52). Correspondingly, SP receptors are expressed on endothelium and muscle of blood and lymphatic vessels, on nerves innervating those vessels, and on associated immune and inflammatory cells (31,36,44).…”

A histologically derived stereotaxic atlas and substance P immunohistochemistry in the brain of the least shrew (Cryptotis parva) support its role as a model organism for behavioral and pharmacological research

“…SP in the central greys, the dorsal horn of the spinal cord, and the trigeminal nuclei/tracts, has been implicated in modulation of nociception, both as a pronociceptive [3,28,29,43] and antinociceptive [18,42] agent, depending on anatomical location. In the dorsal raphe and forebrain, SP has been implicated in the response to stress [8,17].…”

Synaptic Transmission at Functionally Identified Synapses in the Enteric Nervous System: Roles for Both Ionotropic and Metabotropic Receptors

“…While this would be convenient, significant issues need to be resolved before it can be readily accepted. First, tachykinin receptors play a major role in the generation of slow EPSPs involving decreases in K + conductance (see below) and are coupled to both adenylate cyclase and phospholipase C [89] with the latter being the preferred pathway in most instances [106,110]. In fact, some forms of the tachykinin receptors are exclusively coupled to phospholipase C [105].…”