Role of Tachykinins in Asthma and Allergic Disease - New Insights to Neuroimmune Biology - page 166

of the mouse and the human TAC4 gene in lung tissue [28,29] , which may result in
formation of hemokinin 1 and thus represent another source of tachykinins in the
airways.
9.2.1 Airway Tachykinin Receptors
The biological activity of tachykinins depends on their interaction with three spe-
cific receptors: the tachykinin NK 1 , NK 2 , and NK 3 receptors [30] . These receptors
belong to the rhodopsin-like G-protein-coupled receptor family. This group of pro-
teins shares the same structural motif: a bundle of seven hydrophobic transmembrane
domains with three extracellular loops, three intracellular loops, an extracellular
amino terminus, and a cytoplasmic carboxyl terminus [31] . The human tachykinin
NK 1 and NK 2 receptors are proteins of 407 and 398 amino acids, respectively. The
human tachykinin NK 3 receptor is N-terminally extended and has 465 residues [14] .
The tachykinin receptor displaying the highest affinity for substance P was named
the tachykinin NK 1 receptor . The receptor showing the highest affinity for neurokinin
A was termed the tachykinin NK 2 receptor , and the receptor with the highest affin-
ity for neurokinin B was called the tachykinin NK 3 receptor [32,33] . Hemokinin 1
and its elongated forms act as tachykinin NK 1 receptor-preferring agonists [13] . It
should be emphasized that all tachykinins can act as full agonists on the three differ-
ent receptors, but with lower affinities than on the preferred receptor [14] .
The three tachykinin receptors are heterogeneously distributed within each spe-
cies. In addition, there are marked species-related differences in their pattern of
expression. However, they are distributed in the central and peripheral nervous sys-
tems of several species. Their presence can also be demonstrated, functionally or his-
tochemically, in peripheral tissues such as the gastrointestinal tract, urogenital tract,
immune system, cardiovascular system, skin, and skeletal muscle [4] .
An overwhelming amount of functional data indirectly demonstrates the broad
expression of tachykinin NK 1 and NK 2 receptors in the airways. Also, functional
evidence exists for the presence of tachykinin NK 3 receptors [34] . Messenger RNA
for the tachykinin NK 1 and NK 3 receptors has been found in human pulmonary
veins, arteries, and bronchi; mRNA for the tachykinin NK 2 receptor was abundantly
expressed in human bronchi, although only a low expression of this receptor was
found in human pulmonary veins and arteries [35] . In a study on surgical specimens,
using specific antibodies, tachykinin NK 1 and NK 2 receptor proteins were detected in
human bronchial glands, bronchial vessels, and bronchial smooth muscle. Tachykinin
NK 1 receptors were occasionally found in nerves and tachykinin NK 2 receptors
in inflammatory cells, such as T lymphocytes, macrophages, and mast cells [36] . A
study on endobronchial biopsies revealed immunoreactivity for the tachykinin NK 1
receptor in the epithelium and the submucosa. Goblet cells appeared to be the cells
with the strongest staining. In the submucosa, staining was localized to the endothe-
lial cells of the blood vessels, the surfaces of inflammatory cells, and some smooth
muscle cells [22] . Immunohistochemistry on human pulmonary vessels, from tis-
sue obtained at lobectomy, revealed positive staining for tachykinin NK 1 receptors