Tachykinin receptor 1

The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a is_associated_with::G protein coupled receptor found in the is_associated_with::central nervous system and is_associated_with::peripheral nervous system. The is_associated_with::endogenous is_associated_with::ligand for this receptor is is_associated_with::Substance P, although it has some affinity for other is_associated_with::tachykinins. The protein is the product of the TACR1 is_associated_with::gene.

Properties
Tachykinins are a family of is_associated_with::neuropeptides that share the same hydrophobic is_associated_with::C-terminal region with the is_associated_with::amino acid sequence Phe-X-Gly-Leu-Met-NH2, where X represents a is_associated_with::hydrophobic residue that is either an is_associated_with::aromatic or a beta-branched is_associated_with::aliphatic. The is_associated_with::N-terminal region varies between different tachykinins. The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles. is_associated_with::Substance P is the most researched and potent member of the tachykinin family. It is an undecapeptide with the is_associated_with::amino acid sequence Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK1 receptor.

Tachykinin NK1 receptor consists of 407 amino acid residues, and it has a is_associated_with::molecular weight of 58.000. NK1 receptor, as well as the other tachykinin receptors, is made of seven hydrophobic is_associated_with::transmembrane (TM) domains with three is_associated_with::extracellular and three is_associated_with::intracellular loops, an is_associated_with::amino-terminus and a is_associated_with::cytoplasmic is_associated_with::carboxy-terminus. The loops have functional sites, including two is_associated_with::cysteines amino acids for a is_associated_with::disulfide bridge, Asp-Arg-Tyr, which is responsible for association with is_associated_with::arrestin and, Lys/Arg-Lys/Arg-X-X-Lys/Arg, which interacts with is_associated_with::G-proteins.

Distribution and function
The NK1 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 NK1 receptor has been associated with the transmission of stress signals and pain, the contraction of smooth muscles and inflammation. NK1 receptor antagonists have also been studied in migraine, emesis and psychiatric disorders. In fact, is_associated_with::aprepitant has been proved effective in a number of pathophysiological models of anxiety and depression. Other diseases in which the NK1 receptor system is involved include asthma, rheumatoid arthritis and gastrointestinal disorders.

Mechanism
SP is synthesized by neurons and transported to is_associated_with::synaptic vesicles; the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms. When NK1 receptors are stimulated, they can generate various is_associated_with::second messengers, which can trigger a wide range of effector mechanisms that regulate cellular excitability and function. One of those three well-defined, independent is_associated_with::second messenger systems is stimulation, via phospholipase C, of phosphatidyl inositol, turnover leading to Ca mobilization from both intra- and extracellular sources. Second is the is_associated_with::arachidonic acid mobilization via is_associated_with::phospholipase A2 and third is the cAMP accumulation via stimulation of adenylate cyclase. It has also been reported that SP elicits is_associated_with::interleukin-1 (IL-1) production in macrophages, it is known to sensitize neutrophils and enhance is_associated_with::dopamine release in the is_associated_with::substantia nigra region in cat brain. From spinal neurons, SP is known to evoke release of is_associated_with::neurotransmitters like is_associated_with::acetylcholine, is_associated_with::histamine and GABA. It is also known to secrete is_associated_with::catecholamines 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 E2 and is_associated_with::prostacyclin by the arachidonic acid pathway, which leads to an increase in corticosteroid output.

In combination therapy, NK1 receptor antagonists appear to offer better control of delayed emesis and post-operative emesis than drug therapy without NK1 receptor antagonists. NK1 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 NK1 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 target, particularly with regards to potential is_associated_with::analgesics and is_associated_with::anti-depressants. It was identified as a candidate in the etiology of is_associated_with::bipolar disorder by a 2008 study. Furthermore TACR1 antagonists have shown promise for the treatment in alcoholism. Finally TACR1 antagonists may also have a role as novel is_associated_with::antiemetics and is_associated_with::hypnotics.

Selective ligands
Many selective ligands for NK1 are now available, several of which have gone into clinical use as is_associated_with::antiemetics.

Agonists

 * GR-73632 - potent and selective agonist, EC50 2nM, 5-amino acid polypeptide chain. CAS# 133156-06-6

Antagonists

 * is_associated_with::Aprepitant
 * is_associated_with::Casopitant
 * is_associated_with::Ezlopitant
 * is_associated_with::Fosaprepitant
 * Lanepitant
 * is_associated_with::Maropitant
 * is_associated_with::Vestipitant
 * is_associated_with::L-733,060
 * L-741,671
 * L-742,694
 * RP-67580 - potent and selective antagonist, Ki 2.9nM, (3aR,7aR)-Octahydro-2-[1-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