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Functional Studies with Substance P Analogues: Effects of N‐Terminal, C‐Terminal, and C‐Terminus‐Extended Analogues of Substance P on Nicotine‐Induced Secretion and Desensitization in Cultured Bovine Adrenal Chromaffin Cells
Author(s) -
Cheung Nam Sang,
Karlsson Per,
Wang JianXin,
Bienert Michael,
Oehme Peter,
Livett Bruce G.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.62062246.x
Subject(s) - nicotine , endogeny , secretion , nicotinic agonist , substance p , desensitization (medicine) , chemistry , stereochemistry , biochemistry , biology , endocrinology , medicine , neuropeptide , receptor
Substance P (SP) and SP analogues, including C‐terminal, N‐terminal, and C‐terminus‐extended analogues, have been investigated for their ability to modulate nicotine‐induced secretion from bovine adrenal chromaffin cells in culture. Secretion was monitored by measuring the release of endogenous catecholamines by electrochemical detection following separation on HPLC and the release of endogenous ATP with an on‐line luciferin‐luciferase bioluminescence technique. SP is known to have the following two effects on nicotine‐induced secretion of catecholamines (see Livett and Zhou, 1991): inhibition of the nicotinic response and protection against nicotinic desensitization. Secretion induced by 10 ‐5 M nicotine was inhibited 70‐80% by SP, SP‐methyl ester, and the C‐terminus‐extended analogue SP‐Tyr 12 ‐NH 2 , 65% by (Ala 3 )SP‐NH 2 , 45% by the C‐terminal analogue SP(4‐11), and 20 and 5% by the N‐terminal analogues SP(1‐7) and SP(1‐5), respectively, when these peptides were present at 3 ×; 10 ‐5 M concentrations. The order of potency was SP = SP‐methyl ester = SP‐Tyr 12 ‐NH 2 > (Ala 3 )SP‐NH 2 > SP(4‐11) > SP(1‐7) > SP(1‐5). SP, SP‐methyl ester, and (Ala 3 )SP‐NH 2 protected against nicotinic desensitization by 40‐55%, and SP(4‐11) protected by 20% (all at 3 ×; 10 ‐5 M ). In contrast, the N‐terminal analogues SP(1‐7) and SP(1‐5) and the C‐terminus‐extended analogue SP‐Tyr 12 ‐NH 2 at 3 × 10 ‐5 M did not protect against nicotinic desensitization. Cyclo‐SP(3‐9), Ac‐SP(3‐9)‐NH 2 , SP(3‐9), and SP(3‐6) had neither inhibitory nor facilitatory effects on secretion. Of the 20 SP analogues extended at the C terminus by one amino acid, there were only three that protected against nicotinic desensitization, whereas the majority inhibited nicotine‐evoked catecholamine secretion. The present work indicates that for inhibition of nicotine‐evoked secretion, both the C terminus and N terminus of SP are necessary. For the protection against nicotine‐induced desensitization, the C terminus of SP is important. This suggests that the two mechanisms, inhibition of nicotine‐evoked secretion and protection against nicotinic desensitization, are regulated independently.