Disease relevance of Tac1

• We have previously shown early and sustained induction of mRNAs encoding preprotachykinin (PPT) and calcitonin gene-related peptide (CGRP) in dorsal root ganglion (DRG) neurons innervating an inflamed, arthritic joint [1].
• The level of this PPT mRNA was enhanced significantly by 60% during colitis in rat induced by trinitro benzene sulphonic acid [2].
• Stress-induced visceral hypersensitivity in female rats is estrogen-dependent and involves tachykinin NK1 receptors [3].
• Our data support that LPS-induced bronchial hyperreactivity to capsaicin is related closely to the upregulation of tachykinin gene expression, but not the upregulation of NEP [4].
• 5. Thus CP-96,345 is a specific, highly potent, long-acting and orally active inhibitor of tachykinin-mediated neurogenic inflammation [5].

Psychiatry related information on Tac1

• Inhibition of the L-arginine/NO pathway sensitizes the gut to tachykinin-stimulated motor activity [6].
• The intrathecal administration of SR-48,968, a tachykinin NK(2) receptor antagonist, did not affect the visceral pain threshold of hypersensitive animals [7].
• Huntington's disease: changes in tachykinin content in postmortem brains [8].
• Repeated electroconvulsive shock increases tachykinin and cholecystokinin mRNA expression in ventral periaqueductal gray [9].
• Consequently, the present study was conducted to evaluate the hypothesis that the tachykinin neuropeptide K can inhibit maternal behavior after injection into the ventromedial hypothalamus [10].
• Exposure to the forced swim test, an animal model of depression, elevated substance P (SP) release in the lateral septum (LS) of the rat. Acute administration of L-882429 (a neurokinin 1 receptor [ NK1] antagonist) systemically (i.p.) or locally into the LS increased swimming/struggling (active stress-coping strategy; 'antidepressant' effect). This effect was blocked by intraseptal 5-HT(1A) antagonism (WAY-100635). Further experimentation revealed that the effect was most likely mediated by GABAergic interneurons and not a direct heterosynpatic regulation of 5-HT release by NK1 [11].
• Acute (45 minutes) and chronic (10 days;45 minutes each day) immobilization stress both down-regulate NK1 mRNA in the rat hippocampus [12].
• Acute i.p. injections of CP-96,345, SR 48968, and SR 142801 (selective NK1, NK2, and NK3 antagonists, respectively) all decreased immobility in the forced swim test. The antidepressant effects of each antagonist were comparable to two traditional antidepressants, amitriptyline and desipramine. [13]
• The Flinders Sensitive Line (FSL) is an animal model of depression created by selective breeding of Sprague-Dawley rats for increased sensitivity to diisopropylfluorophosphate (DFP; an anticholinesterase). NKA-LI and SP-LI were decreased in striatum but increased in the frontal cortex of FSL rats compared to controls (Flinders Resistant Line rats). In addition, NPY-LI was decreased in the hippocampus of FSL rats. Lithium treatment (admixed in rat chow for six weeks) abolished NKA-LI and SP-LI but not NPY-LI differences. [14]

High impact information on Tac1

• The receptor cDNA was expressed in a mammalian cell line and the ligand binding properties of the encoded receptor were pharmacologically defined by Scatchard analysis and tachykinin peptide displacement as those of a substance P receptor [15].
• Substance P is a member of the tachykinin peptide family and participates in the regulation of diverse biological processes [15].
• Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides [16].
• Thus, hyperosmolarity, but not hypothermia, can directly stimulate tachykinin release from cultured rat sensory C-fibers [17].
• Neurokinin A (1 microM) or B was without effect, implicating NK1 tachykinin receptors [18].

Chemical compound and disease context of Tac1

• SSR240600 inhibited the binding of radioactive substance P to tachykinin NK1 receptors in human lymphoblastic IM9 cells (K(i) = 0.0061 nM), human astrocytoma U373MG cells (K(i) = 0.10 nM), and human brain cortex (IC50 = 0.017 nM) [19].
• These results suggest that both NMDA and NK1 tachykinin receptors are activated in response to peripheral inflammation, but that they may contribute independently to development of hyperalgesia [20].
• The non-peptide tachykinin antagonist, CP-96,345, is a potent inhibitor of neurogenic inflammation [5].
• The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (L-754,030) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluor o)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine and its water soluble prodrug, L-758,298, has been examined against emesis induced by cisplatin in ferrets [21].
• The reverse rank order was found in the tachykinin inhibition of isoproterenol-induced cAMP synthesis and this inhibition was abolished by pertussis toxin, an inactivator of the adenylate cyclase Gi regulatory protein [22].

Biological context of Tac1

• Two overlapping clones contained all of the exons present in beta-PPT, including some 7 and 9 kb 5' and 3' flanking sequence, respectively [23].
• The rat preprotachykinin (PPT) gene encoding the neuropeptides substance P (SP), neurokinin A (NKA), neuropeptide K (NPK), and neuropeptide gamma was isolated from a lambda Charon 4A genomic library [23].
• 3. The inhibitory effect of NKA (1.26 nmol min-1 kg-1) on the acid-induced gastric mucosal vasodilatation was prevented by the tachykinin NK2 receptor antagonists, MEN 10,627 (200 nmol kg-1) but left unaltered by the NK1 receptor antagonist, SR 140,333 (300 nmol kg-1) and the mast-cell stabilizer, ketotifen (4.6 mumol kg-1) [24].
• We have determined the sequences of cDNA clones encoding four variants of PPT mRNA from rat dorsal root ganglion (DRG), including a novel mRNA species (delta-PPT) in which both exons 4 and 6 are absent [25].
• Previous data showed that aging of the central nervous system (CNS) is associated with widespread changes in tachykinin gene expression [26].

Anatomical context of Tac1

• Tachykinin systems in the spinal cord and basal ganglia: influence of neonatal capsaicin treatment or dopaminergic intervention on levels of peptides, substance P-encoding mRNAs, and substance P receptor mRNA [27].
• In addition, we analyzed the expression and regulation of the neutral endopeptidase 24.11 (NEP), the most important enzyme involved in tachykinin degradation in the rat uterus [28].
• Tachykinin-, calcitonin gene-related peptide-, and protein gene product 9.5-immunoreactive nerve fibers in alveolar walls of mammals [29].
• PGP-, TK-, and CGRP-ir fibers were in close spatial relationships to the cells building up the alveolar walls and to alveolar capillaries [29].
• Here, we describe an RNase protection assay that allows the simultaneous quantitation of alternatively spliced PPT mRNAs, Substance P receptor NK-1 mRNA, and glyceraldehyde-3-phosphodehydrogenase (GAPDH) mRNA as an internal control, in the rat hypothalamus [30].

Associations of Tac1 with chemical compounds

• The spinal cord, striatum, or both were used for the quantification of tachykinin [SP and neurokinin A (NKA)] and opioid peptides [[Met5]-enkephalin (ME) and dynorphin A (1-8) (DYN)] by radioimmunoassays [27].
• 4. These findings suggest a role for capsaicin-sensitive primary afferents and the primary afferent neuropeptides encoded by PPT and CGRP mRNA in the maintenance and spread of arthritis [1].
• 1. Following the recent proposal that the selective agonist septide, ([pGlu6,Pro9]SP(6-11)), acts on a novel tachykinin receptor distinct from the 'classical' NK1 receptor, the aim of the study was to investigate the possible heterogeneity of tachykinin NK1 receptors in the rat urinary bladder [31].
• This concept is further supported by the inability of AVP to mimic tachykinin inhibition of the gastric vasodilator response to acid back-diffusion [24].
• Similar interactions were observed between QUIN and tachykinin or metabotropic glutamate agonists [32].

Physical interactions of Tac1

• This result confirms that septide, [pGlu6, Pro9]SP(6-11), a peptide active in the guinea-pig ileum bioassay and practically devoid of binding potencies for the three specific NK-1, NK-2 and NK-3 tachykinin binding sites interacts with a tachykinin receptor different from the NK-1 receptor sensitive to [Pro9]SP [33].
• Longitudinal muscle activity is regulated by excitatory VIP/PACAP/NOS interneurons coupled to cholinergic/tachykinin motor neurons innervating longitudinal muscle [34].

Regulatory relationships of Tac1

• Potentiation of tachykinin-induced plasma protein extravasation by calcitonin gene-related peptide [35].
• This study demonstrates the stability of tachykinin receptors in these peripheral tissues and indicates the suitability of post-mortem tissue as a valid control in future tachykinin receptor studies [36].
• We show that the functional antagonism of dynorphin at the NK4 receptor is reversed by the non-specific opioid antagonist naloxone and that tachykinin-evoked responses at the NK4 receptor are inhibited by the non-peptide NK3 receptor antagonist SR142801 in a concentration dependent manner [37].
• However, the inhibition of Fos expression induced by exogenous substance P indicates that actions at sites postsynaptic to tachykinin- and/or non-tachykinin-containing primary afferent terminals must also contribute to the antinociceptive actions of GABA(B) receptor agonists [38].
• This response remained unchanged after pretreatment with the tachykinin NK1 receptor antagonist SR 140,333 (300 nmol/kg) but tended to be enhanced by the NK2 receptor antagonist MEN 10,627 (200 nmol/kg) [39].

Other interactions of Tac1

• We also studied the effect of a selective inhibitor (captopril, 2.5 mg/kg) of the tachykinin-degrading enzyme kininase II [or angiotensin-converting enzyme (ACE)] on substance P-induced airway vasodilation [40].
• However, on the side ipsilateral to the lesion, NPY, Gal and preprotachykinin (PPT) mRNAs appeared in Mes5 cell bodies [41].
• These results suggest that endothelin-1 selectively inhibits the capsaicin-induced release of neurotransmitters from rat vas deferens and these effects are mediated via endothelin ET(A) receptors but not by tachykinin release [42].
• OBJECTIVES: Present experiments were undertaken to study the influence of peptide NK-1 and NK-2 receptor agonists and antagonists as well as substance P and neurokinin A (the natural ligands for these tachykinin receptors) on vasopressin (AVP) secretion from the rat hypothalamo-neurohypophysial (HN) system in vitro [43].
• To identify epitopes that determine their selectivity for natural and synthetic tachykinin peptides, we constructed a series of chimeric NK1/NK3 receptors in which carboxyl-terminal segments of increasing length in the NK1 receptor were exchanged with the corresponding segments from the NK3 receptor [44].
• SP depressed evoked excitatory postsynaptic currents (EPSCs) in the rat nucleus accumbens (NAc) in vitro and involved PKC and cAMP but not PKA signaling [45]. Morever, the SP-mediated synpatic depression of EPSCs and excitatory evoked postsynaptic potentials in the NAc was blocked by SCH23390 (a D1-like receptor antagonist) and 8-cyclopentyltheophylline (8-CPT; an adenosine A1 receptor blocker) but neither by sulpiride (a selective D2/D3 antagonist) nor by D-APV (a NMDA antagonist) [46]. In addition, SP depressed evoked inhibitory postsynaptic potentials in the NAc, an action which was blocked by SCH23390 and by 8-CPT, suggesting that SP in the NAc modulates both excitatory and inhibitory inputs using similar mechanisms [47].
• WIN51708 (a rat-specific selective NK1 antagonist) did not modulate 5-HT reuptake in rat cortical synaptosomes, indicating that 5-HT transporter inhibition is not likely a mechansm of the assumed antidepressant profile of NK1 antagonists [48].

Analytical, diagnostic and therapeutic context of Tac1

• Using in situ hybridization we found marked increases in expression of beta-preprotachykinin (PPT; 81 +/- 24% rise) and alpha-CGRP (44 +/- 6% rise) mRNAs in innervating (ipsilateral L5) DRG neurones only [49].
• Quantitative receptor autoradiography using several radiolabeled tachykinins was used to localize and characterize tachykinin peptide receptor binding sites in rat CNS and peripheral tissues [50].
• To determine whether the floor plate may respond to substance P we have examined the expression of the principal substance P receptor (the tachykinin NK1 receptor) by floor plate cells of the rat embryonic spinal cord using immunocytochemistry, in situ hybridization and fura-2 calcium imaging [51].
• These findings indicate that estimate of activity of tachykinins and tachykinin related peptides in this bioassay is influenced markedly by peptide degradation via a thiorphan-sensitive mechanism [52].
• We have assessed the effects of tachykinin NK receptor blockade on the injuries following intestinal ischaemia and reperfusion (I/R) in rats [53].

References