Disease relevance of Tac2

• METHODS: To study the effect of sepsis on the spontaneous contractile activity and the contractile responses to norepinephrine (NE), angiotensin II (AT(II)), and neurokinin B (NKB) in the rat portal vein (RPV), we performed a cecal ligature and puncture (CLP) 24 h before RPV isolation [1].
• The increases in NK-3R mRNA in the cerebellum point to the development of receptor supersensitivity and suggest a functional role of NKB in this animal model of epilepsy [2].
• Finally, the ID co-injection of the NK, receptor antagonist SR 142801 significantly inhibited (53%, 76%, 53%, and 100%, respectively) the edema formation caused by NKB and NKA or by SP and senktide [3].
• Similarities of SP-, NKA- and NKB-induced currents in rat dorsal root ganglion neurons [4].
• I.V. injection of 32.5 nmol/kg of NKA, NKA (4-10) and [beta-Ala4, Sar9, Met(O2)11]SP (4-11) raised HR, while NKB and the NK-3 selective agonists produced a rapid and marked bradycardia [5].

Psychiatry related information on Tac2

• Both chronic administration of memantine, and acute administration of NKB, prevented the decline in cortical ChAT activity associated with injection of NMDA into the NBM, and attenuated a reference memory deficit in the radial maze produced by entorhinal cortex lesions [6].
• After five days of water deprivation, AVP mRNA in the PVN and NKB mRNA in both the PVN and the SON increased considerably [7].

High impact information on Tac2

• Substance P (SP) and other related tachykinins such as neurokinin B (NKB) have been studied widely as mediators of sensory information [8].
• The tachykinin NKB has antinociceptive effects in the spinal cord and is contained in intrinsic spinal neurons; thus, NKB may also contribute to the processing of sensory information [8].
• Smaller doses of the antagonists inhibited the effects of SEP compared to NKA, and the effects of NKB could only be antagonized by SPA [9].
• These data suggest that SP receptors are expressed in the brain and peripheral tissues, NK receptors are expressed in the CNS, and SK receptors are expressed in peripheral tissue [10].
• The second type of tachykinin receptor binding site, which is detectable only in the CNS appears to prefer either neuromedin K (NK) and/or substance K (SK) as the endogenous ligand [10].

Chemical compound and disease context of Tac2

• Marked changes in the expression of the tachykinin peptide neurokinin B (NKB) have been recently observed in animal models of epilepsy [2].

Biological context of Tac2

• This receptor binding site is labeled by Bolton-Hunter conjugates of NK, SK, eledoisin, or kassinin and is found in high concentrations in laminae 4 and 5 of the cerebral cortex, the ventral tegmental area, laminae 1 and 2 of the spinal cord, and the inner plexiform layer of the retina [10].
• 4. Cross-tachyphylaxis was not observed with the different neurokinins, but SP and NKA showed novel antagonistic effects on NKB-induced vasodilatation [11].
• Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) increased vascular permeability in a dose-related manner with a threshold dose of about 0.07 pmol in sodium pentobarbitone-anaesthetized animals [12].
• Preferential binding of NKB to endogenous NK(3) receptors affects a variety of biological and physiological processes, including endocrine secretions, sensory transmission, and fluid and electrolyte homeostasis [13].
• Neurokinin B (NKB) also stimulated VO2 (maximum not determined) and vasoconstriction (maximum DeltaPP, 3.40 +/- 0.25 mm Hg; EC50, 34.4 +/- 5.2 nM) [14].

Anatomical context of Tac2

• Ligand-binding displacement in membranes of mammalian COS cells transfected with the cDNA indicated the rank order of affinity of the receptor to tachykinins: neuromedin K greater than substance K greater than substance P [15].
• Injection of the mRNA synthesized in vitro from the cloned cDNA into Xenopus oocytes elicited electrophysiological responses to tachykinins, with the most potent sensitivity being to neuromedin K [15].
• In bioassay experiments, FK 224 inhibited SP-induced contraction of guinea pig ileum (NK1) and NKA-induced contraction of rat vas deferens (NK2) in a dose-dependent manner, but did not affect NKB-induced contraction of rat portal vein (NK3) [16].
• NK3 receptor-immunoreactive neurons were found in the basal forebrain region including the substantia innominata, where axon terminals immunoreactive for preprotachykinin B, the precursor peptide of neurokinin B (NKB), were densely distributed [17].
• Our data suggest a widespread and distinct distribution of neurons expressing NKB within the central nervous system, suggesting possible neuromodulatory roles of this neuropeptide for various brain functions [18].

Associations of Tac2 with chemical compounds

• Competition studies indicated the following rank order of potencies among tachykinins: NKB greater than eledoisin (E) greater than kassinin greater than physalaemin greater than neurokinin A (NKA) greater than substance P (SP), a result suggesting that NKB might be the endogenous ligand for [3H]NKB binding sites [19].
• Bath application of the NK(1) receptor agonist substance P (SP) or the NK(3) receptor agonists senktide and NKB induced a robust increase in "spontaneous" excitatory postsynaptic currents (EPSCs) in 5-HT neurons [20].
• Additionally, hyporesponsiveness to AT(II) and NKB was not modified by indomethacin [1].
• Infusions of the endogenous NK-3 ligand, NKB (3.0 pmol in 1.0 microliter), also elicited hyperactivity equivalent to that produced by an equimolar dose of senktide [21].
• However, substance K, neuromedin K and physalaemin also exhibited limited cross-reactions with the antiserum [22].

Other interactions of Tac2

• Neuromedin K: a novel mammalian tachykinin identified in porcine spinal cord [23].

Analytical, diagnostic and therapeutic context of Tac2

• These data fit well with radioimmunoassay data that suggest that, whereas in the CNS SP, SK and NK are present in high concentrations, in peripheral tissues only SP and SK are present in detectable concentrations [10].
• Searching for possible sites of action of NKB in the central nervous system, we have now investigated its distribution within the rat brain by immunohistochemical techniques and in situ hybridization [18].
• Cholinergic neurons expressing neuromedin K receptor (NK3) in the basal forebrain of the rat: a double immunofluorescence study [24].
• The distribution of neurokinin B (NKB) was determined by immunocytochemistry with antisera directed toward its amino terminus [25].
• Characterization of these tachykinins using HPLC and gel-filtration columns revealed that C18 columns did not adequately separate NPK from NKB under the conditions used by previous authors [26].

References