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Received for publication April 29, 2004.
Revised August 19, 2004.
Accepted for publication August 19, 2004.
The catestatin fragment of chromogranin A is an endogenous inhibitor of nicotinic cholinergic transmission, functioning in negative-feedback control of catecholamine secretion. We explored naturally occurring polymorphism in the amino acid sequence of catestatin. Three human variants were identified: Gly364Ser, Pro370Leu, and Arg374Gln. Variants were tested for ability to inhibit four nicotinic processes. The rank order of potency for inhibition of catecholamine secretion was Pro370Leu > wild-type > Gly364Ser > Arg374Gln. Decrease in potency was paralleled by decline in Hill slope, suggesting that negative cooperativity at ascending dose might underlie loss of potency. Several lines of evidence indicated that each variant acted as a nicotinic antagonist: potency to inhibit secretion paralleled inhibition of agonist-triggered 22Na+ uptake (r=0.986); variants inhibited secretion with similar potency when triggered by several nicotinic agonists, though not by agents utilizing other secretory pathways or bypassing the nicotinic receptor; and blockade of secretion was non-competitive with agonist. Variants also inhibited desensitization of secretion after prior agonist exposure, and stimulation of secretory protein biosynthesis by agonist. Rank order of variant inhibitory potency for all four nicotinic processes was identical (Pro370Leu > wild-type > Gly364Ser > Arg374Gln), suggesting mediation by similar combinations of receptor 
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subunits, and that crucial catestatin residues are likely to be identical across the four processes. When catestatin variants were mixed in likely heterozygotic 50:50 combinations, the inhibitory curve was left-shifted onto that of the more potent variant in the combination, suggesting phenotypic dominance. The results have quantitative implications for inter-individual variations in human nicotinic signaling.
Key words:
Neuropeptides, Nicotinic cholinergic, Structure-activity relationships and modeling, Regulation of gene expression, Structure/function/mechanism, Exocytosis
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