Substance P enhances cholinergic receptor desensitization in a

Substance P inhibits carbamylcholine-induced 22Na+ uptake in the clonal cell line PC12. This inhibition is noncompetitive with agonist but competitive with Na+. Oc- tahydrohistrionicotoxin (HI-HTX) also ex-hibits this same pattern of inhibition. Moreover, both substance P and H8-HTX are very effective in enhancing agonist-induced receptor desensitization. Local anesthetics, such as QX222, also cause inhibition that is competitive with Na+, but they have only marginal effects on desensitization. Because substance P and H8-HTX cannot by themselves cause desensitization, their action is dependent on and synergistic with the action of agonist. Furthermore, sub- stance P and H-HTX do not appear to compete for the same site as QX222, which is thought to bind to the ion channel. Finally, substance P can stabilize the desensitized state of the receptor even when added subsequent to the actual desensitization and removal of agonist. Thus, substance P does not require open ion channels for binding and may modulate the activity ofthe re- ceptor-ionophore complex by binding to a distinct regulatory site.