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PNAS 98 (23): 13049-13054

Copyright © 2001 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell

Thomas C. Rich*, Kent A. Fagan{dagger}, Tonia E. Tse*, Jerome Schaack{ddagger}, Dermot M. F. Cooper{dagger}, and Jeffrey W. Karpen*,§

Departments of *Physiology and Biophysics, {dagger}Pharmacology, and {ddagger}Microbiology, University of Colorado Health Sciences Center, Denver, CO 80262

Received for publication July 23, 2001.

Abstract: cAMP, the classical second messenger, regulates many diverse cellular functions. The primary effector of cAMP signals, protein kinase A, differentially phosphorylates hundreds of cellular targets. Little is known, however, about the spatial and temporal nature of cAMP signals and their information content. Thus, it is largely unclear how cAMP, in response to different stimuli, orchestrates such a wide variety of cellular responses. Previously, we presented evidence that cAMP is produced in subcellular compartments near the plasma membrane, and that diffusion of cAMP from these compartments to the bulk cytosol is hindered. Here we report that a uniform extracellular stimulus initiates distinct cAMP signals within different cellular compartments. By using cyclic nucleotide-gated ion channels engineered as cAMP biosensors, we found that prostaglandin E1 stimulation of human embryonic kidney cells caused a transient increase in cAMP concentration near the membrane. Interestingly, in the same time frame, the total cellular cAMP rose to a steady level. The decline in cAMP levels near the membrane was prevented by pretreatment with phosphodiesterase inhibitors. These data demonstrate that spatially and temporally distinct cAMP signals can coexist within simple cells.

§ To whom reprint requests should be addressed at: Department of Physiology and Biophysics, Box C-240, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262. E-mail: jeffrey.karpen{at}uchsc.edu.

Edited by Bertil Hille, University of Washington, Seattle, WA, and approved September 5, 2001

This paper was submitted directly (Track II) to the PNAS office.

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