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Regulation of human neutrophil guanylate cyclase by metal ions, free radicals and the muscarinic cholinergic receptor

Lad, P. M. and Glovsky, M. M. and Richards, J. H. and Smiley, P. A. and Backstrom, B. (1985) Regulation of human neutrophil guanylate cyclase by metal ions, free radicals and the muscarinic cholinergic receptor. Molecular Immunology, 22 (7). pp. 731-739. ISSN 0161-5890. doi:10.1016/0161-5890(85)90138-5.

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We have examined the properties of soluble guanylate cyclase activity in the human neutrophil. The enzyme showed complex regulation by metal ions. A 10-fold higher activity was observed in the presence of Mn^(2+) than Mg^(2+), while Ca^(2+) caused an increase in activity only in the presence of Mg^(2+) ion. Sodium nitroprusside (SNP), azide and hydrogen peroxide were activators of the enzyme. Dithiothreitol blocked the activation by SNP, suggesting the involvement of thiol groups in the activation process. Carbachol acting through the muscarinic cholinergic receptor caused a dose-dependent activation, which was blocked by atropine. Higher concns of carbachol were required to activate guanylate cyclase than were required for the modulation of enzyme release elicited by N-fortnyl-L-methionyl-L-leucyl-L-phenylalanine. Nordihydroguaracetic acid inhibited carbachol stimulation of guanylate cyclase. By contrast, trifluoperazine (TFP), a calmodulin antagonist, caused a biphasic modulation of basal activity in the presence or absence of carbachol. Our results indicate that: (a) allosteric interactions of metal ions are important to the regulation of the enzyme, (b) the free radical nitroxide as well as hydrogen peroxide enhances enzyme activity, (c) agonist occupancy of the muscarinic cholinergic receptor activates neutrophil guanylate cyclase probably through a mechanism involving calcium influx and the activation of the lipoxygenase pathway, and (d) a TFP-sensitive site (possibly calmodulin) is involved in the selective regulation of basal enzyme activity.

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Additional Information:© 1985 Pergamon Press Ltd. Received 17 August 1984; accepted 10 September 1984. We thank Aline Alenty for advice in neutrophil function tests. We are also grateful to Lauren Rosenthal and Bill Frankenberger for secretarial assistance. This work was supported by grants from the Southern California Permanente Medical Group, and a Biomedical Research support grant RR-05521-19 from the Kaiser Foundation Research Institute. P.M.L. is the recipient of grants AM30878 and AM34550 from the NTH and a grant from the American Heart Association, in support of this work.
Funding AgencyGrant Number
Southern California Permanente Medical GroupUNSPECIFIED
Kaiser Foundation Research InstituteRR-05521-19
American Heart AssociationUNSPECIFIED
Issue or Number:7
Record Number:CaltechAUTHORS:20150505-084710345
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Official Citation:P.M. Lad, M.M. Glovsky, J.H. Richards, P.A. Smiley, B. Backstrom, Regulation of human neutrophil guanylate cyclase by metal ions, free radicals and the muscarinic cholinergic receptor, Molecular Immunology, Volume 22, Issue 7, July 1985, Pages 731-739, ISSN 0161-5890, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:57217
Deposited By: Tony Diaz
Deposited On:05 May 2015 16:47
Last Modified:10 Nov 2021 21:09

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