We have identified a novel peptide, catestatin (bovine chromogranin A [CgA]344-364: RSMRLSFRARGYGFRG PGLQL; human CgA352-372: SSMKLSFRARGYGFRGPGPQL), which is a potent inhibitor of nicotinic cholinergicstimulated catecholamine secretion, desensitization of catecholamine release and transcription of chromogranin A (Chga) gene. Although the homology modeling of bovine catestatin suggested a β-strand / loop / b-strand active conformation, 2-D 1H-NMR studies of linear human catestatin (hCgA352-372) exhibited a loosely coiled loop conformation in solution. This peptide is stored within and secreted from chromaffin granules. Catestatin displays characteristic inhibitory effects on nicotinic cationic (Na+, Ca 2+) signal transduction and the effects are specific to the neuronal nicotinic receptor. Results from artificial mutants of catestatin defined an active catestatin core (bovine CgA344-358) as well as the roles of crucial amino acid residues for inhibition of nicotinic cholinergic-stimulated catecholamine secretion and agonist desensitization. Utilizing systematic polymorphism discovery at the human CgA locus we discovered three human variants of catestatin: Gly364Ser, Pro 370Leu, and Arg374Gln that displayed the following rank order of potency for inhibition of catecholamine secretion: Pro 370Leu > wild-type > Gly364Ser > Arg374Gln. Treatment with nicotine augmented expression of the Chga / luciferase transgene and the increment was inhibited >90% by catestatin, establishing an entirely new role for the peptide on gene expression in vivo. Diminished catestatin is observed in hypertensive individuals as well as early-normotensive offspring of patients with hypertension, suggesting that an early deficiency of catestatin might play a pathogenic role in the subsequent development of the disease.