Desensitization of Catecholamine Release

Abstract

Nicotinic cholinergic receptors undergo desensitization upon repeated or prolonged exposure to agonist. We investigated the effects of a novel chromogranin A catecholamine release-inhibitory fragment, catestatin (chromogranin A_344–364), on agonist-induced desensitization of catecholamine release from pheochromocytoma cells. In a dose-dependent fashion, the nicotinic antagonist catestatin blocked agonist desensitization of both catecholamine release (IC₅₀ ∼ 0.24 μm) and²²Na⁺ uptake (IC₅₀ ∼ 0.31 μm), the initial step in nicotinic cationic signal transduction; both secretion inhibition and blockade of desensitization were noncompetitive with agonist. Desensitizing effects of the nicotinic agonists nicotine and epibatidine were blocked. This antagonist action was specific to desensitization by nicotinic agonists, since catestatin did not block desensitization of catecholamine release induced by agents which bypass the nicotinic receptor. Hill plots with slopes near unity suggested noncooperativity for catestatin effects on both nicotinic responses (secretory antagonism and blockade of desensitization). Human, bovine, and rat catestatins (as well as substance P) had similar potencies. IC₅₀ values for secretion inhibition and blockade of desensitization paralleled each other (r = 0.76,n = 10 antagonists, p = 0.01) for several noncompetitive nicotinic antagonists. Peptide nicotinic antagonists (catestatins, substance P) were far more potent inhibitors of both secretion (p = 0.019) and desensitization (p = 0.005) than nonpeptide antagonists (trimethaphan, hexamethonium, procaine, phencyclidine, cocaine, or clonidine), and the peptides displayed enhanced selectivity to block desensitization versus secretion (p = 0.003). We conclude that catestatin is a highly potent, dose-dependent, noncompetitive, noncooperative, specific inhibitor of nicotinic desensitization, an effect which may have implications for control of catecholamine release.