Neurokinin A receptor

Tachykinin NK2 receptor TK NK2r Neurokinin-2 receptor, neurokinin A receptor, substance K receptor, neurokinin-alpha receptor, Neuromedin L receptor... 

Takeda, Y., Blount, P., Sachais, B. S., Hershey, A. D., Raddatz, R., Krause, J. E. Ligand binding kinetics of substance P and neurokinin A receptors stably expressed in Chinese hamster ovary cells and evidence for differential stimulation of inositol 1,4,5-trisphosphate and cyclic AMP second messenger responses, J. Neurochem. 1992, 59, 740-745. 

Palanche, T., Ilien, B., Zoffmann, S., Reck, M. P., Bucher, B., Edelstein, S. J., and Galzi, J. L. (2001). The neurokinin a receptor activates calcium and camp responses through distinct conformational states. J. Biol. Chem. 276, 34853-34861. 

C-fibre afferents from the aitways contain peptide tachykinin transmitters such as substance P (SP) and neurokinins A and B (NKA and NKB). Stimulation of these nerves can also cause local release of these mediators at their peripheral terminal, allowing them to enhance the activity of the RARs. SP, NKA and NKB act at the tachykinin receptors (NK4-NK3), and so understandably, antagonists for NK2 in particular appear promising in cough. 

Substance P is a member of a group of polypeptides known as neurokinins or tachykinins. It is thought to be the primary neurotransmitter for the transfer of sensory information from the periphery to the spinal cord and brain. Substance P as well as neurokinin NKX receptors has been detected in vagal afferent neurons in the area postrema, nucleus tractus solitarius and dorsal motor nucleus of the vagus. Substance P has been shown to increase the firing rate of neurons in the area postrema and nucleus tractus solitarius and to produce retching when applied directly to these areas in animal studies. 

The common C-terminal amino acid sequence required for exerting activity at tachykinin receptors is shown in bold endokinin C and D lack the C-terminal Met and are almost devoid of affinity at these receptors. In red, the sequence of neurokinin A of which neuropeptide-gamma and neuropeptide-kappa are elongated forms and neurokinin A (3-10) is a product of beta or gamma-TAC1 mRNAs or an NKA metabolite active at tachykinin receptors. In blue, the sequence of human HK-1 of which endokinin A and B are elongated forms. 

Neurokinin-1 Receptor. A homology model of the neurokinin-1 (NKi) receptor was built from the X-ray structure of rhodopsin, using the MOBILE (modeling binding sites including ligand information explicitly) approach. In this procedure, a preliminary model is generated, which is afterwards refined... 

Evers A, Klebe G. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. J Med Ghent 2004 47 5381-92. 

Some propeptides lead to the production of different, in terms of receptor affinities, peptides (substance P and neurokinin A act on neurokinin 1 and 2 receptors, respectively). 

Different peptides from the same gene product (met and leu enkephalin, substance P and neurokinin A). The former two act on the same receptor, the delta opioid receptor, whereas the latter act on different receptors, the neurokinin 1 and 2 receptors. Despite this, the receptors for the neurokinins produce the same direction of effect, a slow depolarisation, even though their distribution differs. 

These are a family of peptides which include substance P, isolated in 1931 but only sequenced in 1971. This peptide has been extensively studied since it was the first major peptide to be extracted from brain but only now are useful antagonists becoming available. Two closely related peptides were then isolated from mammalian tissues and can be added to a number of other tachykinins, many of which are found in amphibians. The name tachykinins originated from the vasoactive effects of substance P but the nomenclature has been resolved into calling the three major mammalian peptides substance P, neurokinin A (NKA) and neurokinin B (NKB) with the corresponding receptors being numbered 1 to 3. The order of potencies at the three receptors as follows ... 

TRPVl also plays a central role in intercellular pro-inflammatory feedback loops. An important example is mast cells and sensory nerves. Mast cells release tryptase that, in turn, activates the protease-activated receptor PAR-2 activation of PAR-2 then opens TRPVl via PKC [50]. In keeping with this, PAR-2 agonists reduce the heat activation threshold of TRPVl from 42 °C to below body temperature [51]. Excited nerve endings release SP that, as a positive feedback, binds to neurokinin NKl receptors on mast cells. Mast cells also express TRPVl [52]. Consequently, endovanilloids can act in concert to stimulate mast cells and activate capsaicin-sensitive nerve endings. Of relevance is the finding that PAR-2 is up-regulated in the bladder during experimental cystitis [53]. 

Smith, B. J., Doran, A. C., Mclean, S., Tingley III, F. D., O Neil, C. A., Kajiji, S. M., P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists, J. Pharmacol. Exp. Ther. 2001, 298, 1252-1259. 

Non-peptidic tachykinine antagonists were converted to photoprobe ligands by Ward. First, a piperidine derivative, CP-99,994 (Glaxo) was appended with a diazirine photophore (6, Fig. 7) to study SP (NK1) receptors [74]. A similar modification on a neurokinin A antagonist, SR 48968 (Sanofi) produced a photoligand (5, Fig. 7) in order to investigate NK2 receptor proteins [75]. 

A5 and C primarily project to lamina II and V of the dorsal horn, where they synapse onto local interneurons or directly onto upward-projecting neurons (figure 8.1). These primary afferents release a number of neurotransmitters to relay pain, including glutamate, aspartate, substance P, neurokinin A and B, and calcitonin gene-related peptide (table 8.1). NMDA, non-NMDA and neurokinin receptors are involved in re-... 

The oocyte system has also been utilized by Turcatti et al. to incorporate a fluorescent amino acid into the tachykinin neurokinin-2 receptor (NK2), al-... 

Other more recent examples of new receptor subt)rpes include neurokinin, melanocortin and somatostatin receptor subt)q)es. Neurokinins (substance P, neurokinin A and neurokinin B) act at three receptor subtypes NK, NK2 and NK3. Selective ligands are being... 

Although substance P (SP) and its receptor, neurokinin 1 receptor (NKIR), have been implicated in the control of mood, anxiety, and stress, the efficacy of NK1R antagonists as both antidepressants and anxiolytics has been matter of considerable debate (Lesch 2001a). Santarelh and associates (2001) have recently made a strong argument for a critical role of the SP/NKIR system the modu-... 

Santarelli L, Gobbi G, Debs PC, Sibfile EL, Blier P, Hen R, Heath MJS (2001) Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function. Proc Natl Acad Sci U S A 98 1912-1917... 

Figure 4.3 Schematic representation of a 7-transmembrane receptor, exemplified with the human neurokinin-1 receptor (hNK,) The extracellular elements of the receptor are shown in the upper part the amino-acid chain ends with a free amino-residue (NH2) and is called the amino-terminal of the receptor. The longer amino acid chain of the intracellular part (lower part) ends with a free acid-residue (COOH) and is called the carboxylic end. The seven transmembrane domains are lined up within the box, which represents the membrane...

File, S.E. Anxiolytic action of a neurokinin-1 receptor antagonist in the social interaction test. Pharmacol. Biochem. Behav. 58, 747-752, 1997. 

Substance P (SP) is a member of the family of tachykinin peptides that also includes neurokinin A and B. Their respective receptors are tachykinin NKl, tachykinin NK2 and tachykinin NK3. Substance P is best known as a pain neurotransmitter, but it also controls vomiting. In relation to emesis, its sites of localisation include the area postrema and the nucleus tractus solitarius. 

The actions of substance P and neurokinins A and are mediated by three G protein-coupled tachykinin receptors designated NK i, NK 2, and NK 3. Substance P is the preferred ligand for the NK receptor, the predominant tachykinin receptor in the human brain. However, neurokinins A and also possess considerable affinity for this receptor. In humans, most of the central and peripheral effects of substance P are mediated by NKi receptors. All three receptor subtypes are coupled to inositol trisphosphate synthesis and calcium mobilization. 

Substance P and neurokinin 1 receptors. The first neurokinin was discovered in the 1930s in extracts of brain or intestine. Since it was prepared as a powder, it was called substance P. This molecule is now known to be a string of 11 amino acids (an undecapeptide) (Fig. 5—67). This is in sharp contrast to monoamine neurotransmitters, which are modifications of a single amino acid. 

FIGURE 5—68. Substance P neurons and neurokinin 1 receptors, part 1. For neurons utilizing substance P, synthesis starts with the gene called pre-protachykinin A (PPT-A). This gene is transcribed into RNA, which is then edited to form three alternative mRNA splice variants, alpha, beta, and gamma. The actions of the mRNA version called alpha-PPT-A mRNA are shown here. This mRNA is then transcribed into a protein called alpha-PPT-A, which is substance P s grandparent. It is converted in the endoplasmic reticulum into the parent of substance P, called protachykinin A (alpha-PT-A). Finally, this protein is clipped even shorter by another enzyme, called a converting enzyme, in the synaptic vesicle and forms substance P itself. 

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