The existence of a third tachykinin receptor (SP‐N) in the mammalian nervous system was demonstrated by development of highly selective agonists. Systematic N‐methylation of individual peptide bonds in the C‐terminal hexapeptide of substance P gave rise to agonists which specifically act on different receptor subtypes. The most selective analog of this series, succinyl‐[Asp6,Me‐Phe8]SP6‐11, elicits half‐maximal contraction of the guinea pig ileum through the neuronal SP‐N receptor at a concentration of 0.5 nM. At least 60,000‐fold higher concentrations of this peptide are required to stimulate the other two tachykinin receptors (SP‐P and SP‐E). The action of selective SP‐N agonists in the guinea pig ileum is antagonized by opioid peptides, suggesting a functional counteraction between opiate and SP‐N receptors. These results indicate that the tachykinin receptors are distinct entities which may mediate different physiological functions.
Receptor specificity of the substance P-related peptides neurokinin A and neurokinin B was studied in the isolated guinea pig ileum. Substance P and the recently discovered neurokinins elicit contraction of the ileum both directly through action on a muscle cell receptor and indirectly through stimulation of a neuronal receptor, leading to release of acetylcholine, which causes muscle contraction via muscarinic receptors. Two specific assay procedures for the function of the neuronal receptor were developed. The muscular receptor was inactivated either by desensitization with the selective agonist substance P methyl ester or by receptor blockade with the selective antagonist [Arg6, D-Trp7,9, MePhe8Jsubstance P-(461) hexapeptide. Both procedures revealed that the neuronal receptor is clearly distinct from the muscular receptor, since it exhibits different agonist specificity and is insensitive to antagonists of the muscular receptor.Neurokinin B was found to be the most potent agonist (ECse = 1 nM) for the neuronal receptor. Furthermore, [D-Ala2, Metslenkephalinamlde inhibited in a naloxone-sensitive manner the effect of neurokinin B mediated via the neuronal receptor. These results suggest that the different mammalian tachykinins can play specific physiological roles by virtue of their distinct receptor specificities.The tachykinins are a family of biologically active peptides
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