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PMID: 16247029 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Termination of cAMP signals by Ca2+ and G(alpha)i via extracellular Ca2+ sensors: a link to intracellular Ca2+ oscillations.

The Journal of cell biology ·Vol. 171 ·No. 2 ·2005-10-24 ·Pages 303-12

Gerbino A, Ruder WC, Curci S, Pozzan T, Zaccolo M, Hofer AM

Abstract

Termination of cyclic adenosine monophosphate (cAMP) signaling via the extracellular Ca(2+)-sensing receptor (CaR) was visualized in single CaR-expressing human embryonic kidney (HEK) 293 cells using ratiometric fluorescence resonance energy transfer-dependent cAMP sensors based on protein kinase A and Epac. Stimulation of CaR rapidly reversed or prevented agonist-stimulated elevation of cAMP through a dual mechanism involving pertussis toxin-sensitive Galpha(i) and the CaR-stimulated increase in intracellular [Ca2+]. In parallel measurements with fura-2, CaR activation elicited robust Ca2+ oscillations that increased in frequency in the presence of cAMP, eventually fusing into a sustained plateau. Considering the Ca2+ sensitivity of cAMP accumulation in these cells, lack of oscillations in [cAMP] during the initial phases of CaR stimulation was puzzling. Additional experiments showed that low-frequency, long-duration Ca2+ oscillations generated a dynamic staircase pattern in [cAMP], whereas higher frequency spiking had no effect. Our data suggest that the cAMP machinery in HEK cells acts as a low-pass filter disregarding the relatively rapid Ca2+ spiking stimulated by Ca(2+)-mobilizing agonists under physiological conditions.

MeSH Terms
Acetylcysteine/analogs & derivatives,metabolism Biosensing Techniques/methods Calcium/metabolism,pharmacology Calcium Signaling/drug effects,physiology Cell Line Cell Membrane/drug effects,metabolism Cyclic AMP/antagonists & inhibitors,biosynthesis,metabolism Cyclic AMP-Dependent Protein Kinases/metabolism Erythromycin/analogs & derivatives,metabolism Fluorescence Resonance Energy Transfer/methods GTP-Binding Protein alpha Subunits, Gi-Go/antagonists & inhibitors,metabolism,pharmacology Humans Pertussis Toxin/pharmacology Receptors, Calcium-Sensing/drug effects,physiology Sensitivity and Specificity Signal Transduction/drug effects,physiology
Chemicals
Receptors, Calcium-Sensing Erythromycin erythromycin propionate-N-acetylcysteinate Cyclic AMP Pertussis Toxin Cyclic AMP-Dependent Protein Kinases GTP-Binding Protein alpha Subunits, Gi-Go Calcium Acetylcysteine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Gerbino Andrea
Veterans' Affairs Boston Healthcare System, West Roxbury, MA 02132, USA.
Ruder Warren C
Curci Silvana
Pozzan Tullio
Zaccolo Manuela
Hofer Aldebaran M
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200507054
Published
2005-10-24
Pages
303-12
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2171199
Subset
IM
Grants
Telethon · TCP00089 · Italy
External Links
PubMed source DOI: 10.1083/jcb.200507054 PMC Full Text View journal details
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