Transglutaminase-Synthesized γ-(Glutamyl⁵) Spermidine Derivative of Substance P Is a Selective Tool for Neurokinin-2 Receptors Characterization

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• 作者：Mancuso ; Franca ; Costa ; Claudia ; Calignano ; Antonio ; Mariniello ; Loredana ; Rossi ; Francesco ; et. al.
• 关键词：Substance P ; Transglutaminase ; Spermidine ; Polyamines ; Bronchoconstriction ; NK₂ receptor subtypes
• 刊名：Peptides
• 出版年：1998
• 出版时间：April, 1998
• 年：1998
• 卷：19
• 期：4
• 页码：683-690
• 全文大小：117 K

文摘

The ability of transglutaminase-synthesized 1,3-diaminopropane, spermidine (Spd), spermine (Spm), and monodansylcadaverine γ-(glutamyl⁵)derivatives of substance P (SP) to produce bronchoconstriction was investigated. In urethane-anaesthetized guinea pigs, intravenous injections of SP derivatives contracted differently bronchial smooth muscle and caused hypotension. The most effective bronchoconstrictor among SP analogs was the γ-(glutamyl⁵)Spd derivative of SP (Spd-SP; EC₅₀ = 5.3 nmol/kg), which was more potent than the native peptide (EC₅₀ = 26.5 nmol/kg). In contrast, the γ-(glutamyl⁵)Spm derivative of SP (Spm-SP) was found completely unable to cause bronchoconstriction and was significantly less effective than SP in determining hypotension. The contractile effect of Spd-SP and Spm-SP was investigated in vitro on rat isolated colon, a well-characterized preparation rich in NK₂ receptors. In addition, Spd-SP was tested on the endothelium-denuded rabbit pulmonary artery (RPA) and the hamster isolated trachea (HT), both tissue preparations containing only a single functional receptor subtype (NK_2A and NK_2B, respectively). The results obtained showed that Spd-SP recognizes NK₂ receptors occurring on rat isolated colon more effectively (EC₅₀ = 11 nM) than the native peptide (EC₅₀ = 45 nM). Conversely, Spm-SP evokes a contractile response less effective than that elicited by SP (EC₅₀ = 312 nM). Furthermore, Spd-SP (0.1–10 μg kg⁻¹) produced a concentration-dependent contraction of both HT and RPA, exhibiting a potency respectively 12 and 30 times higher than SP in contracting HT and RPA. Our results indicate that the introduction of a Spd moiety at the level of glutamine-5 of SP gives rise to an analog that possesses a different capability to recognize NK₂ receptors than the parent peptide. Moreover, since Spd-SP seems to contract more effectively RPA than HT, we conclude that it preferentially recognizes the NK_2A receptor subtype.