The Mammalian Tachykinin Ligand-Receptor System: An Emerging Target for Central Neurological Disorders

Abstract

Our understanding of the complex signaling neurophysiology of the central nervous system has facilitated the exploration of potential novel receptor-ligand system targets for disorders of this most complex organ. In recent years, many relatively neglected receptor-ligand systems have been re-evaluated with respect to their ability to potently modulate discrete tracts in the central nervous system. One such system is the tachykinin (previously neurokinin) system. The multiple heptahelical G protein-coupled receptors and neuropeptide ligands that comprise this system may be significantly involved in more central nervous systems actions than previously thought, including sleep disorders, amyotrophic lateral sclerosis, Alzheimer’s and Machado-Joseph disease. The development of our understanding of the role of the tachykinin receptor-ligand system in higher order central functions is likely to allow the creation of more specific and selective tachykinin-related neurotherapeutics.

The Tachykinin Peptide Neurokinin B Binds Copper Forming an Unusual [CuII(NKB)2] Complex and Inhibits Copper Uptake into 1321N1 Astrocytoma Cells

“…39 + , m/z 2420.1; calcd 2420.0). The addition of copper at either 0.5 or 1.0 equiv results in the appearance of only a very small peak at m/z 2483.0, which is consistent with [Cu II (NKB) 2 + H] + , although the low intensity precludes accurate identification (data not shown). The lack of a reasonable copper-bound peak suggests that the complex either does not ionize well or is insufficiently stable to persist during the ionization process.…”

“…4 Functionally, the tachykinins are involved in a diverse range of cellular signaling processes including roles in neuroprotection, neuroinflammation, and neurotrophic pathways. 1,2,5 Much of our understanding of tachykinin function is due to research on the first member identified, SP, and the roles of NKA and NKB have remained more elusive. Recently though, NKB has been identified as a key molecule in normal reproductive function.…”

“…6,7 The tachykinins and their receptors are predominantly expressed in the central nervous system (CNS), although they do have peripheral nervous system (PNS) expression and are observed in other organs. 2,8 Of the main mammalian peptides, SP has both CNS and PNS expression, NKB is almost exclusively found in the CNS, 9 and NKA is largely expressed in the PNS. In the CNS, SP, NKB, and their receptors are highly expressed in regions of the brain that are important for cognition and emotion, 10,11 and antagonists for NK3-R are currently being pursued as therapeutics in a range of disorders including schizophrenia.…”

“…In the CNS, SP, NKB, and their receptors are highly expressed in regions of the brain that are important for cognition and emotion, 10,11 and antagonists for NK3-R are currently being pursued as therapeutics in a range of disorders including schizophrenia. 12,13 The tachykinins have a well-documented involvement in several neurodegenerative disorders, particularly Alzheimer's disease (AD); 2 for example, AD patients appear to have diminished SP expression, 14 and there is also evidence that NKB has a role. Studies have shown that both NKB and SP appear to be able to protect neurons against the toxic effects of Aβ peptides.…”

Substance P induces gastric mucosal protection at supraspinal level via increasing the level of endomorphin-2 in rats

“…Substance P is encoded by the tachykinin precursor 1 (TAC1) gene, originally known as preprotachykinin (PPT)-A or PPT-I and represents the major endogenous ligand for the neurokinin receptor 1 (NK1), though it possesses appreciable affinity also for the other two tachykinin receptor subtypes, NK2 and NK3 (Harrison and Geppetti, 2001;Pantaleo et al, 2010).…”