Neurokinin 1

8 Pages·1.316 MB·English

by  Weinstock J.V.

Neurokinin 1
Joel V. Weinstock*
Division of Gastroenterology-Hepatology, Department of Medicine, University of Iowa, 4607 JCP,
Iowa City, IA 52242, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2001.23011.
SUMMARY 1970s, reports suggested that rat synaptic membranes
displayed high-affinity binding sites for substance P.
TheNK1receptorisaGprotein-coupled,seventrans- TheaminoacidsequenceoftheratNK1receptorwas
membrane receptor. The gene and mRNA encoding deduced by molecular cloning in 1989 (Yokota et al.,
the NK1 receptor have been cloned from several 1989). The structure of the first highly specific,
species.SubstancePisthenaturalhigh-affinityligand nonpeptide NK1 antagonist was published in 1991
for this receptor. The receptor desensitizes then (Snider et al., 1991).
gradually resensitizes following repeat substance P
exposure. The NK1 receptor is displayed extensively
Alternative names
throughoutthebody.Itappearsprominentlyinvarious
regionsofthebrain,spinalcord,lungs,andintestines.
It is expressed on neurons, vascular endothelium, Substance P receptor.
intestinalepithelium,lymphocytesandothercelltypes
oftheimmunesystem.Intheimmunesystem,various
Structure
cytokines as well as T cell receptor engagement can
induce NK1 expression. Stimulation of the NK1
receptor excites several distinct intracellular second TheNK1receptor isamemberofthesuperfamilyof
messenger systems. Activation of the receptor affects G protein-coupled seven transmembrane receptors
immunoregulation,cardiorespiratoryphysiology,neu- (OhkuboandNakanishi,1991).Hydrophobicdomains
rotransmission, and intestinal secretion and absorp- form (cid:11) helices that span the cell membrane seven
tion. It also influences neuronal survival and helps times. Figure 1 shows the potential N-glycosylation
regulatetheemeticreflex,variousbehavioralresponses, sites (triangles) and conserved amino acids (solid
vascular dilatation, and vascular permeability. There circles) among the three tachykinin receptors (NK1,
are several nonpeptide NK1 receptor antagonists NK2, NK3) and a possible palmitoylation site repre-
undergoing clinical evaluation for management of sented by a zigzag line. The intracytoplasmic
emesis, depression, and other pathophysiological C-terminal conformation presumably determines the
processes. typeofbiologicalactivitydisplayed.Theactualthree-
dimensional structure is unknown.
Main activities and
BACKGROUND
pathophysiological roles
Discovery
The wide distribution of the NK1 receptor and sub-
Substance P is the natural high-affinity ligand of the stantial additional evidence suggest that this receptor
NK1 receptor. Substance P was purified and hasmanyfunctions(QuartaraandMaggi,1997).The
sequenced in 1971 (Chang et al., 1971). In the late NK1 receptor is involved in pain transmission in
CytokineReference Copyright#2001AcademicPress
2 Joel V. Weinstock
Figure 1 Model of the NK1 receptor. system inflammation in response to Trypanosoma
bruceiinfection(Kennedyetal.,1997).
Mouse models demonstrate that activation of the
NK1 receptor can significantly upregulate immune
inflammatory reactions. However, the importance of
NK1 receptors in human disease is unknown. There
are no known diseases directly attributed to loss or
overexpression of the NK1 receptor.
Published Assays and Other Research Tools for
Studying the NK1 Receptor
1. Monoclonal and polyclonal antibodies for NK1
receptor identification via immunohistochemistry.
2. AutoradiographiclocalizationofNK1receptorsin
tissue sections.
3. Polyclonal antibody for Western blot identifica-
tion of receptor protein.
4. PCR (Blum et al., 2000; murine) and RNase pro-
tection(GautreauandKerdelhue,1998;rat)assays
for quantification of receptor mRNA. The PCR
peripheral nerves and the spinal cord (Mantyh et al.,
assay can detect and measure <100 NK1 receptor
1997), and in expression of neurogenic inflammation
mRNA transcripts in 0.3(cid:22)g of total RNA.
(McDonald et al., 1996). In the CNS, it influences
5. Highly selective human and murine nonpeptide
neuronal survival and helps to regulate the emetic
NK1 receptor antagonists.
reflex, cardiovascular, and respiratory functions, and
6. NK1 receptor knockout mouse on 129(cid:2)C57BL/6,
variousbehavioralresponses.Otherfunctionsinclude
C57BL/6, and CBA backgrounds.
stimulation of vasodilatation and enhancement of
7. Various human and murine cell lines (i.e. lympho-
vascular permeability. In addition, it has a role in
cytes,macrophages)thatexpresstheNK1receptor.
intestinal secretion, motility, and neuro-neuronal
communication.
While substance P has various immunoregulatory GENE
functions(Maggi,1997),theroleoftheNK1receptoris
less clearly defined because substance P may bind to
Accession numbers
other receptors in addition to NK1. However, recent
publications clearly implicate the NK1 receptor in
Human gene: X65177, X65178, X65179, X65180,
immune modulation and susceptibility to infection.
X65181
StudiesinvivoandinvitrousingspecificNK1receptor
Human mRNA: M76675
antagonistsandmicedeficientinNK1receptorshave
Rat gene: M64232, M64233, M64235, M64236,
showntheimportanceofthisreceptorinmediatingthe
M34751, M34752, M34754, M34755
T cell IFN(cid:13) response in murine schistosomiasis
Rat mRNA: M31477
(WeinstockandElliott,1998).Thisregulationisviaa
Mouse mRNA: X62934
NK1 receptor located on the T cell. Mice pretreated
with a substance P receptor antagonist are more
susceptible to intestinal salmonellosis, showing a Sequence
decreasedIFN(cid:13) responseintheintestine(Kincy-Cain
andBost,1996).Clostridiumdifficileisabacteriumthat See Figures 2, 3, 4, 5, and 6. Sequence data beyond
canreleasetoxins,whichinducescolitisinhumans.The that shown here is available at: www.ncbi.nlm.nih.
NK1 receptor helps to mediate the inflammatory gov/.
diarrhea and mucosal injury induced by C. difficile
toxin A (Castagliuolo et al., 1998). Mice with
Chromosome location and linkages
disruptionoftheNK1receptorgenearelesssusceptible
toimmunecomplex-induced,pulmonaryinjury(Bozic
et al., 1996) and IL-1-induced, neutrophil migration A single gene encodes the NK1 receptor. In humans,
(Ahluwalia et al., 1998). Mice receiving an NK1 it is located on chromosome 2 (Gerard et al., 1991).
receptorantagonistdeveloplessseverecentralnervous Reports suggest that mammalian tissue also may
Neurokinin 1 3
Figure2 Humangenesequence.Thecompletesequencesofthefiveexonsandpartialsequencesofthefourintronsare
shown. The TATA box is in bold (1339–1342) and the exons are underlined (Takahashi et al., 1992).
variations do not affect substance P binding or
produceatruncatedisoformoftheNK1receptorthat signaling. However, they do explain species-depen-
is of unknown physiological significance. dent variation in potency of various pharmacological
receptor antagonists.
PROTEIN
Accession numbers
Human, rat, and mouse NK1 receptors all contain
407aminoacids.Thededucedaminoacidsequenceof SwissProt:
the rat is 99% identical to that of the mouse, but Human: P25103
differs by 22 residues from that of human. These Mouse: P30548
4 Joel V. Weinstock
Sequence Relevant homologies and species
differences
See Figure 7.
The mammalian tachykinin system consists of three
Figure 3 Human mRNA sequence (Gerard et al., 1991).
distinct peptides called substance P, neurokinin A,
and neurokinin B. Their receptors are designated
NK1, NK2, and NK3, respectively. The three
receptors share homology (Table 1). The substance
P receptor (NK1) also can bind neurokinin A and
neurokinin B.
Affinity for ligand(s)
Substance P binds the NK1 receptor with high
affinity (K <10(cid:255)9M). The rank order of affinity for
i
the various tachykinins for the substance P NK1
binding site is substance P(cid:29)neurokinin
Figure4 Ratgenesequence(Hersheyetal.,1991).Completesequencesofthefiveexonsandpartialsequencesofthefour
introns. Exons are underlined. Source: rat (strain Fisher) DNA. The chromosome origin is unknown.
Neurokinin 1 5
Figure 5 Rat mRNA sequence (Hershey and Krause, Figure 7 Amino acid sequences for NK1 receptor of
1990). human (protein ID: CAA46292.1, PID: g825721, GI:
825721, SwissProt: P25103), rat (protein ID:
AAB59726.1, PID: g1196819, GI: 1196819), and mouse
(protein ID: CAA44707.1, PID: g54207, GI: 54207,
MGD:MGI: 98475, SwissProt: P30548). The seven trans-
membrane domains are underlined.
Figure 6 Mouse mRNA sequence (Sundelin et al., 1992).
The chromosome origin is unknown.
Table 1 Homology among the tachykinin receptor sub-
types
NK1 NK2 NK3
Amino acid 407 390 452
residues
Molecular 46,364 43,851 51,104
weight
Homology 54% to NK2 55% to NK2
in amino 66% to NK3
acid sequence
A>neurokinin B. However, it recently has been could not fully differentiate NK1 receptor binding
suggested that the NK1 receptor actually has two from among the other tachykinin receptors. There is
distinct high-affinity binding sites, one for substance strong evidence, however, that the NK1 receptor is
P and one for neurokinin A. The latter site is located displayed extensively in various regions of the brain
at least in part at the distal end of the second and spinal cord. It also is expression on vascular
extracellular loop (Wijkhuisen et al., 1999). The endothelial cells (Greeno et al., 1993). In various
bindingsiteforsubstancePappearstorequireregions regions of the intestines, there are NK1-binding sites
of transmembrane domains I, II, and VII, and the in the smooth muscle layers, submucosa, epithelium
N-terminus (Berthold and Bartfai, 1997). and ganglia of the enteric plexuses. The renal pelvis,
ureter, bladder, and pulmonary microvasculature
(Bowden et al., 1996) are other probable sites of
Cell types and tissues expressing NK1 receptor expression. The salivary glands also
have NK1 receptors.
the receptor
Lymphoid organs and immunocytes can express
NK1 receptors. There are NK1 receptors in germinal
In many instances, the precise location and cellular centers of mesenteric lymph nodes and in intestinal
distribution of NK1 receptors remain controversial. lymphoid tissue. Reports suggest that lymphocytes
Many of the techniques used and reagent employed and macrophages can express this receptor in both
6 Joel V. Weinstock
human and other mammalian species (Cook et al., experimental cell systems can excite various second
1994; Ho et al., 1997; Goode et al., 1998). messenger pathways. Ligand binding can activate
phospholipase C and D (Torrens et al., 1998). This
generates I(1,4,5)P and increases [Ca2+]. Also
Regulation of receptor expression 3
activated are arachidonic acid release, adenylyl
cyclase and phospholipase A2(1,2,3) (Grady et al.,
At least in some cells, desensitization followed 1995).
by gradual re-sensitization is the physiological
response to repeat substance P exposure. Studies
using Chinese hamster ovary (CHO) cells and other
receptor-transfected cell lines suggest that NK1 THERAPEUTIC UTILITY
receptor desensitization following substance P
engagement requires receptor phosphorylation. G Effect of treatment with soluble
protein-coupled receptor kinases like GRK2
receptor domain
(Nishimura et al., 1998) phosphorylate the receptor,
while (cid:12)-arrestins uncouple the phosphorylated recep-
torfromtheheterotrimericGproteins(McConalogue There are several nonpeptide NK1 receptor antago-
etal.,1999;Baraketal.,1999).Thisterminatessignal nists undergoing clinical evaluation. Reports suggest
transduction.Therearereportsofasecondisoformof that they may prove useful for controlling depression
theNK1receptorthatistruncatedattheC-terminus. (Krameretal.,1998),emesis(Navarietal.,1999)and
When transfected into CHO cells, this receptor does exercise-induced bronchoconstriction in asthma
not undergo rapid and prolonged desensitization (Ichinose et al., 1996).
upon exposure to substance P (Li et al., 1997).
Substance P also stimulates clathrin-mediated
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8 Joel V. Weinstock
Wijkhuisen,A.,Sagot,M.A.,Frobert,Y.,Creminon,C.,Grassi, ACKNOWLEDGEMENTS
J.,Boquet,D.,andCouraud,J.Y.(1999).Identificationinthe
NK1tachykininreceptorofadomaininvolvedinrecognitionof
Grants from the National Institutes of Health
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447,155–159. (DK38327, DK07663, DK25295), the Crohn’s and
Yokota, Y., Sasai, Y., Tanaka, K., Fujiwara, T., Tsuchida, K., ColitisFoundationofAmerica,Inc.andtheVeterans
Shigemoto, R., Kakizuka, A., Ohkubo, H., and Nakanishi, S.
Administration supported this research.
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