The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a
G protein coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
found in the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
and
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
. The
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
for this receptor is
Substance P
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clos ...
, although it has some affinity for other
tachykinin
Tachykinin peptides are one of the largest families of neuropeptides, found from amphibians to mammals. They were so named due to their ability to rapidly induce contraction of gut tissue. The tachykinin family is characterized by a common C-termi ...
s. The protein is the product of the ''TACR1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Properties
Tachykinins are a family of
neuropeptide
Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
s that share the same
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
region with the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
sequence
Phe-X-
Gly
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
-
Leu-
Met-NH
2, where X represents a
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
residue that is either an
aromatic
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
or a beta-branched
aliphatic
In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, or ...
. The
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
region varies between different tachykinins.
The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles.
Substance P
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clos ...
(SP) is the most researched and potent member of the tachykinin family. It is an undecapeptide with the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
sequence
Arg
Arg or ARG may refer to:
Places
*''Arg'' () means "citadel" in Persian, and may refer to:
**Arg, Iran, a village in Fars Province, Iran
**Arg (Kabul), presidential palace in Kabul, Afghanistan
**Arg, South Khorasan, a village in South Khorasan P ...
-
Pro
Pro is an abbreviation meaning "professional".
Pro, PRO or variants thereof may also refer to:
People
* Miguel Pro (1891–1927), Mexican priest
* Pro Hart (1928–2006), Australian painter
* Mlungisi Mdluli (born 1980), South African retired f ...
-
Lys-
Pro
Pro is an abbreviation meaning "professional".
Pro, PRO or variants thereof may also refer to:
People
* Miguel Pro (1891–1927), Mexican priest
* Pro Hart (1928–2006), Australian painter
* Mlungisi Mdluli (born 1980), South African retired f ...
-
Gln-
Gln-
Phe-
Phe-
Gly
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
-
Leu-
Met-NH
2.
SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK
1 receptor.
Tachykinin NK
1 receptor
consists of 407 amino acid residues, and it has a
molecular weight
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
of 58,000.
NK
1 receptor, as well as the other tachykinin receptors, is made of seven hydrophobic
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
(TM) domains with three
extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
and three
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
loops, an
amino-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
and a
cytoplasmic
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...
carboxy-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. The loops have functional sites, including two
cystein
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
es amino acids for a
disulfide bridge
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
,
Asp-
Arg
Arg or ARG may refer to:
Places
*''Arg'' () means "citadel" in Persian, and may refer to:
**Arg, Iran, a village in Fars Province, Iran
**Arg (Kabul), presidential palace in Kabul, Afghanistan
**Arg, South Khorasan, a village in South Khorasan P ...
-
Tyr, which is responsible for association with
arrestin
Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors.
Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of ...
and,
Lys/
Arg
Arg or ARG may refer to:
Places
*''Arg'' () means "citadel" in Persian, and may refer to:
**Arg, Iran, a village in Fars Province, Iran
**Arg (Kabul), presidential palace in Kabul, Afghanistan
**Arg, South Khorasan, a village in South Khorasan P ...
-
Lys/
Arg
Arg or ARG may refer to:
Places
*''Arg'' () means "citadel" in Persian, and may refer to:
**Arg, Iran, a village in Fars Province, Iran
**Arg (Kabul), presidential palace in Kabul, Afghanistan
**Arg, South Khorasan, a village in South Khorasan P ...
-X-X-
Lys/
Arg
Arg or ARG may refer to:
Places
*''Arg'' () means "citadel" in Persian, and may refer to:
**Arg, Iran, a village in Fars Province, Iran
**Arg (Kabul), presidential palace in Kabul, Afghanistan
**Arg, South Khorasan, a village in South Khorasan P ...
, which interacts with
G-proteins
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
.
Distribution and function
The NK
1 receptor can be found in both the central and peripheral nervous system. It is present in neurons, brainstem, vascular endothelial cells, muscle, gastrointestinal tracts, genitourinary tract, pulmonary tissue, thyroid gland and different types of immune cells.
The binding of SP to the NK
1 receptor has been associated with the transmission of stress signals and pain, the contraction of smooth muscles and inflammation.
NK
1 receptor antagonists have also been studied in migraine, emesis and psychiatric disorders. In fact,
aprepitant
Aprepitant, sold under the brand name Emend among others, is a medication used to prevent chemotherapy-induced nausea and vomiting (CINV) and to prevent postoperative nausea and vomiting (PONV). It may be used together with ondansetron and de ...
has been proved effective in a number of pathophysiological models of anxiety and depression.
Other diseases in which the NK
1 receptor system is involved include asthma, rheumatoid arthritis and gastrointestinal disorders.
Mechanism
SP is synthesized by neurons and transported to
synaptic vesicles
In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impul ...
; the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms.
When NK
1 receptors are stimulated, they can generate various
second messengers
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
, which can trigger a wide range of effector mechanisms that regulate cellular excitability and function. One of those three well-defined, independent
second messenger systems
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
is stimulation, via
phospholipase C
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
, of phosphatidyl inositol, turnover leading to Ca mobilization from both intra- and extracellular sources. Second is the
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
mobilization via
phospholipase A2
The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glyce ...
and third is the
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
accumulation via stimulation of adenylate cyclase.
It has also been reported that SP elicits
interleukin-1
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Discovery
Discovery of these cytokines began with studies on t ...
(IL-1) production in macrophages, it is known to sensitize neutrophils and enhance
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
release in the
substantia nigra
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...
region in cat brain. From spinal neurons, SP is known to evoke release of
neurotransmitters
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neur ...
like
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
,
histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
and
GABA. It is also known to secrete
catecholamines
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a substi ...
and play a role in the regulation of blood pressure and hypertension. Likewise, SP is known to bind to
N-methyl-D-aspartate (NMDA) receptors by eliciting excitation with calcium ion influx, which further releases nitric oxide. Studies in frogs have shown that SP elicits the release of prostaglandin E
2 and
prostacyclin
Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
When used as a drug, it is also known as epoprosteno ...
by the arachidonic acid pathway, which leads to an increase in corticosteroid output.
In combination therapy, NK
1 receptor antagonists appear to offer better control of delayed emesis and post-operative emesis than drug therapy without NK
1 receptor antagonists. NK
1 receptor antagonists block responses to a broader range of emetic stimuli than the established
5-HT3 antagonist treatments.
It has been reported that centrally-acting NK
1 receptors antagonists, such as CP-99994, inhibit emesis induced by apomorphine and loperimidine, which are two compounds that act through central mechanisms.
Clinical significance
This receptor is considered an attractive
drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
target
Target may refer to:
Physical items
* Shooting target, used in marksmanship training and various shooting sports
** Bullseye (target), the goal one for which one aims in many of these sports
** Aiming point, in field artillery, fi ...
, particularly with regards to potential
analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
s and
anti-depressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, heada ...
s.
It is also a potential treatment for alcoholism and
opioid addiction
Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Op ...
.
In addition, it has been identified as a candidate in the etiology of
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
.
Finally NK1R antagonists may also have a role as novel
antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...
s
and
hypnotic
Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...
s.
Ligands
Many selective ligands for NK
1 are now available, several of which have gone into clinical use as
antiemetics
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be ...
.
Agonists
* GR-73632 - potent and selective agonist, EC
50 2nM, 5-amino acid polypeptide chain. CAS# 133156-06-6
Antagonists
*
Aprepitant
Aprepitant, sold under the brand name Emend among others, is a medication used to prevent chemotherapy-induced nausea and vomiting (CINV) and to prevent postoperative nausea and vomiting (PONV). It may be used together with ondansetron and de ...
*
Casopitant
Casopitant (), former tentative trade names Rezonic (U.S.) and Zunrisa (Europe), is an NK1 receptor antagonist which was undergoing research for the treatment of chemotherapy-induced nausea and vomiting. It was under development by GlaxoSmithKli ...
*
Elinzanetant
Elinzanetant (developmental code names BAY-3427080 GSK-1144814, NT-814) is an orally active small-molecule neurokinin/tachykinin NK1 receptor and NK3 receptor antagonist which is under development by Bayer, GlaxoSmithKline, and NeRRe Therapeu ...
*
Ezlopitant
Ezlopitant (INN, code name CJ-11,974) is an NK1 receptor antagonist. It has antiemetic and antinociceptive effects. Pfizer was developing ezlopitant for the treatment of irritable bowel syndrome but it appears to have been discontinued.
See ...
*
Fosaprepitant
Fosaprepitant (Emend for Injection (US), Ivemend (EU)) is an antiemetic medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent d ...
* Lanepitant
*
Maropitant
Maropitant (INN; trade name: Cerenia ), used as maropitant citrate (USAN), is a neurokinin-1 (NK1) receptor antagonist developed by Zoetis specifically for the treatment of motion sickness and vomiting in dogs. It was approved by the FDA in 200 ...
*
Vestipitant
Vestipitant (INN) is a drug developed by GlaxoSmithKline which acts as a selective antagonist for the NK1 receptor. It is under development as a potential antiemetic and anxiolytic drug, and as a treatment for tinnitus and insomnia.
See also
...
*
L-733,060
L-733,060 is a drug developed by Merck & Co., Merck which acts as an orally active, non-peptide, selective Receptor antagonist, antagonist for the Tachykinin receptor 1, NK1 Receptor (biochemistry), receptor, binding with a Dissociation constant, ...
* L-741,671
* L-742,694
* RP-67580 - potent and selective antagonist, Ki 2.9nM, (3aR,7aR)-Octahydro-2-
-imino-2-(2-methoxyphenyl)ethyl 7,7-diphenyl-4H-isoindol, CAS# 135911-02-3
* RPR-100,893
* CP-96345
* CP-99994
* GR-205,171
* TAK-637
* T-2328
See also
*
NK1 receptor antagonist
Neurokinin 1 (NK1) antagonists (-pitants) are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. NK-1 antagonists boost the efficacy of 5-HT3 antagonists to prevent nausea and vomiting. The dis ...
*
Tachykinin receptor
There are three known mammalian tachykinin receptors termed NK1, NK2 and NK3. All are members of the 7 transmembrane G-protein coupled receptor family and induce the activation of phospholipase C, producing inositol triphosphate (so called Gq- ...
*
Discovery and development of neurokinin 1 receptor antagonists
References
Further reading
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External links
*
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{{Obsessive–compulsive disorder
G protein-coupled receptors
Molecular neuroscience
Biology of bipolar disorder