The catecholamine release-inhibitory "catestatin" fragment of chromogranin a: naturally occurring human variants with different potencies for multiple chromaffin cell nicotinic cholinergic responses.
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 polymorphisms 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 (22)Na(+) uptake (r = 0.986); variants inhibited secretion with similar potency when triggered by several nicotinic agonists, though not by agents using other secretory pathways or bypassing the nicotinic receptor; and blockade of secretion was noncompetitive 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 alpha/beta subunits and that crucial catestatin residues are likely to be identical across the four processes. When catestatin variants were mixed in likely heterozygotic (1:1 M ratio) 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 interindividual variations in human nicotinic signaling.
Mahata
Sushil K
SK
Department of Medicine and Center for Molecular Genetics, University of California, San Diego, CA 92093-0838, USA. smahata@ucsd.edu.
Mahata
Manjula
M
Wen
Gen
G
Wong
William B
WB
Mahapatra
Nitish R
NR
Hamilton
Bruce A
BA
O'Connor
Daniel T
DT
D000595:Amino Acid Sequence; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism; D053379:Chromogranin A; D002864:Chromogranins / Q000235:genetics / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
C506150:CHGA protein, human; D002395:Catecholamines; D053379:Chromogranin A; D002864:Chromogranins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C109084:chromogranin A (344-364); C506153:chromogranin A, rat; D009538:Nicotine