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J. Biol. Chem., Vol. 276, Issue 40, 37124-37132, October 5, 2001
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From the Department of Neurobiology, Pharmacology and Physiology,
The University of Chicago, Chicago, Illinois 60637
The interplay between activated G proteins and
intracellular calcium ([Ca2+]i) in the
regulation of secretion was studied in the macrophage, coupling
membrane capacitance with calcium-sensitive microfluorimetry.
Intracellular elevation of either the nonhydrolyzable analogue of GTP,
guanosine-5'-O-(3-thiotriphosphate) (GTP
Calcium-G Protein Interactions in the Regulation of
Macrophage Secretion*
S), or
[Ca2+]i enhanced the amplitude and shortened the
time course of stimulus-induced secretion in a
dose-dependent manner. Both the ionophore- and the
stimulus-induced secretory response were abolished in the presence of
guanosine-5'-O-(2-thiodiphosphate) (GDP
S). The
Kd of Ca2+-driven secretion was
independent of GTPS concentration, whereas the
Kd of the GTPS-driven response decreased from 63 to 31 µM in the presence of saturating concentrations of
[Ca2+]i. The time course of stimulus-induced
secretion was dependent upon the concentration of
[Ca2+]i. The time course of GTPS-driven
secretion was concentration-independent at high levels of
[Ca2+]i, suggesting that a
calcium-dependent translocation/binding step was
rate-limiting. Our data strongly support a model in which [Ca2+]i and activated G proteins act
independently of one another in the sequential regulation of macrophage
secretion. [Ca2+]i appears to play a role in the
recruitment and priming of vesicles from reserve intracellular pools at
a step that is upstream of G protein activation. While activated, G
proteins appear to play a key role in fusion of docked vesicles. Thus, secretion can result either from activating more G proteins or from
elevating [Ca2+]i at basal levels of G protein activation.
*
This work was supported by NIGMS, National Institutes of
Health Grant RO1 GM36823.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: University of Chicago,
Dept. of Neurobiology, Pharmacology, and Physiology, 947 E. 58th St.,
MC 0926, Chicago, IL 60637. Tel.: 773-702-0126; Fax: 773-834-4522;
E-mail: dnelson@drugs.bsd.uchicago.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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