Abstract
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.
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