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Department of Medicine and Center for Molecular Genetics (S.K.M.,
M.M., D.T.O.) University of California, and Veterans Affairs
San Diego Healthcare System San Diego, California 92161
Department of Pharmacology (A.R.W.) Wayne State University
School of Medicine Detroit, Michigan 48201
The novel chromogranin A fragment catestatin
(bovine chromogranin
A344-364;
RSMRLSFRARGYGFRGPGLQL) is a potent inhibitor of catecholamine release
(IC50, 
0.2–0.3
µM) by acting as a nicotinic cholinergic
antagonist. To define the minimal active region within catestatin, we
tested the potencies of synthetic serial three-residue deletion
(amino-terminal, carboxyl-terminal, or bidirectional) fragments to
inhibit nicotine-stimulated catecholamine secretion from PC12
pheochromocytoma cells. The results revealed that a completely
active core sequence of catestatin was constituted by chromogranin
A344-358. Nicotinic
cationic signal transduction was affected by catestatin fragments in a
manner similar to that for secretion (confirming the functional
importance of the amino-terminus). To identify crucial residues within
the active core, we tested serial single amino acid truncations or
single residue substitutions by alanine on
nicotine-induced catecholamine secretion and
desensitization. Nicotinic inhibition by the active catestatin core was
diminished by even single amino acid deletions. Selective alanine
substitution mutagenesis of the active core revealed important roles
for Met346, Leu348,
Phe350, Arg351,
Arg353, Gly354,
Tyr355, Phe357, and
Arg358 on catecholamine secretion, whereas
crucial roles to inhibit desensitization of catecholamine release were
noted for Arg344,
Met346, Leu348,
Ser349, Phe350,
Arg353, Gly354,
Tyr355, Gly356, and
Arg358. We conclude that a small, 15-amino acid
core of catestatin (chromogranin
A344-358) is
sufficient to exert the peptide’s typical inhibitory effects on
nicotinic cholinergic-stimulated catecholamine secretion, signal
transduction, and desensitization. These studies refine the
biologically active domains of catestatin and suggest that the
pharmacophores for inhibition of nicotinic secretion and
desensitization may not be identical.
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