Structure-activity relationship for substance P inhibition of carbamylcholine-stimulated 22Na+ flux in neuronal (PC12) and non-neuronal (BC3H1) cell lines.
The inhibition of carbamylcholine-stimulated 22Na+ flux by substance P and various peptide analogs was examined in PC12 cells, a line which contains a neuronal-type nicotinic receptor, and BC3H1 cells, a line which contains a muscle-type nicotinic receptor. Substance P produces a noncompetitive inhibition of carbamylcholine-stimulated 22Na+ influx in both cell lines (IC50 = 1.2 microM on PC12 cells and 8.2 microM on BC3H1 cells). The structure-activity relation for substance P analogs was qualitatively similar in both cell lines; however, there were quantitative differences. Substance P was the most potent peptide tested. Analogs of substance P with amino acids removed from the N-terminus resulted in significant decreases in potency, whereas removal of amino acids from the C-terminus resulted in analogs virtually devoid of activity. Compounds purported to be substance P antagonists had actions similar to substance P in reducing carbamylcholine-stimulated 22Na+ flux. The related tachykinins physalaemin and eledoisin had low potencies on both cell lines. These results indicate that the site through which substance P exerts its inhibitory effects on activation of nicotinic receptors is different from the receptors described previously for substance P in more classical systems. In addition, our results indicate that substance P has an effect on both the neuronal-type nicotinic receptor (alpha-bungarotoxin insensitive) expressed on PC12 cells and the muscle-type nicotinic receptor (alpha-bungarotoxin sensitive) expressed on BC3H1 cells.
Simasko
S M
SM
Soares
J R
JR
Weiland
G A
GA
D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D002460:Cell Line; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects; D012964:Sodium / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D011978:Receptors, Nicotinic; D013373:Substance P; D002217:Carbachol; D012964:Sodium