Novel autocrine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist.
Catecholamine secretory vesicle core proteins (chromogranins) contain an activity that inhibits catecholamine release, but the identity of the responsible peptide has been elusive. Size-fractionated chromogranins antagonized nicotinic cholinergic-stimulated catecholamine secretion; the inhibitor was enriched in processed chromogranin fragments, and was liberated from purified chromogranin A. Of 15 synthetic peptides spanning approximately 80% of chromogranin A, one (bovine chromogranin A344-364 [RSMRLSFRARGYGFRGPGLQL], or catestatin) was a potent, dose-dependent (IC50 approximately 200 nM), reversible secretory inhibitor on pheochromocytoma and adrenal chromaffin cells, as well as noradrenergic neurites. An antibody directed against this peptide blocked the inhibitory effect of chromogranin A proteolytic fragments on nicotinic-stimulated catecholamine secretion. This region of chromogranin A is extensively processed within chromaffin vesicles in vivo. The inhibitory effect was specific for nicotinic cholinergic stimulation of catecholamine release, and was shared by this chromogranin A region from several species. Nicotinic cationic (Na+, Ca2+) signal transduction was specifically disrupted by catestatin. Even high-dose nicotine failed to overcome the inhibition, suggesting noncompetitive nicotinic antagonism. This small domain within chromogranin A may contribute to a novel, autocrine, homeostatic (negative-feedback) mechanism controlling catecholamine release from chromaffin cells and neurons.
Mahata
S K
SK
Department of Medicine and Center for Molecular Genetics, University of California, San Diego, California 92093, USA.
O'Connor
D T
DT
Mahata
M
M
Yoo
S H
SH
Taupenot
L
L
Wu
H
H
Gill
B M
BM
Parmer
R J
RJ
D000595:Amino Acid Sequence; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D019898:Autocrine Communication; D017609:Barium Compounds / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000032:analysis / Q000493:pharmacokinetics; D002417:Cattle; D002712:Chlorides / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D019439:Chromaffin Cells / Q000737:chemistry; D053379:Chromogranin A; D002864:Chromogranins / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry* / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012964:Sodium / Q000493:pharmacokinetics; D013045:Species Specificity; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology
D019138:Antibodies, Blocking; D017609:Barium Compounds; C506150:CHGA protein, human; D002712:Chlorides; D053379:Chromogranin A; D002864:Chromogranins; D018733:Nicotinic Antagonists; D009842:Oligopeptides; D010446:Peptide Fragments; D018048:Receptors, Purinergic P2; C109084:chromogranin A (344-364); C506153:chromogranin A, rat; C024986:barium chloride; C074912:N(alpha)-(N(alpha)-(N(alpha)-(tert-butyloxycarbonyl)glutaminyl)-N(1)-formyl-tryptophyl)phenylalanine benzyl ester; D013373:Substance P; D000001:Calcimycin; D011189:Potassium Chloride; D009538:Nicotine; D002738:Chloroquine; D012964:Sodium; D002118:Calcium; D009638:Norepinephrine