QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 14 February 2006
doi: 10.1242/jcs.02812

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.02812v1 119/5/828    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Willoughby, D. Articles by Cooper, D. M. F. Search for Related Content PubMed PubMed Citation Articles by Willoughby, D. Articles by Cooper, D. M. F. Social Bookmarking                         What's this?

Ca²⁺ stimulation of adenylyl cyclase generates dynamic oscillations in cyclic AMP

Department of Pharmacology, Tennis Court Road, University of Cambridge, CB2 1PD, UK

^* Author for correspondence (e-mail: dmfc2{at}cam.ac.uk)

Accepted 15 November 2005

The spatial and temporal complexity of Ca²⁺ signalling is central to the regulation of a diverse range of cellular processes. The decoding of dynamic Ca²⁺ signals is, in part, mediated by the ability of Ca²⁺ to regulate other second messengers, including cyclic AMP (cAMP). A number of kinetic models (including our own) predict that interdependent Ca²⁺ and cAMP oscillations can be generated. A previous study in Xenopus neurons illustrated prolonged, low-frequency cAMP oscillations during bursts of Ca²⁺ transients. However, the detection of more dynamic Ca²⁺ driven changes in cAMP has, until recently, been limited by the availability of suitable cAMP probes with high temporal resolution. We have used a newly developed FRET-based cAMP indicator comprised of the cAMP binding domain of Epac-1 to examine interplay between Ca²⁺ and cAMP dynamics. This probe was recently used in excitable cells to reveal an inverse relationship between cAMP and Ca²⁺ oscillations as a consequence of Ca²⁺-dependent activation of phosphodiesterase 1 (PDE1). Here, we have used human embryonic kidney (HEK293) cells expressing the type 8 adenylyl cyclase (AC8) to examine whether dynamic Ca²⁺ changes can mediate phasic cAMP oscillations as a consequence of Ca²⁺-stimulated AC activity. During artificial or agonist-induced Ca²⁺ oscillations we detected fast, periodic changes in cAMP that depended upon Ca²⁺ stimulation of AC8 with subsequent PKA-mediated phosphodiesterase 4 (PDE4) activity. Carbachol (10 µM) evoked cAMP transients with a peak frequency of 3 minute^-1, demonstrating phasic oscillations in cAMP and Ca²⁺ in response to physiological stimuli. Furthermore, by imposing a range of Ca²⁺-oscillation frequencies, we demonstrate that AC8 acts as a low-pass filter for high-frequency Ca²⁺ events, enhancing the regulatory options available to this signalling pathway.

Key words: Calcium, cAMP, Oscillation, Adenylyl cyclase, Phosphodiesterase

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				D. A. MacDougall, S. Wachten, A. Ciruela, A. Sinz, and D. M. F. Cooper Separate Elements within a Single IQ-like Motif in Adenylyl Cyclase Type 8 Impart Ca2+/Calmodulin Binding and Autoinhibition J. Biol. Chem., June 5, 2009; 284(23): 15573 - 15588. [Abstract] [Full Text] [PDF]

				A. C. L. Martin, D. Willoughby, A. Ciruela, L.-J. Ayling, M. Pagano, S. Wachten, A. Tengholm, and D. M. F. Cooper Capacitative Ca2+ Entry via Orai1 and Stromal Interacting Molecule 1 (STIM1) Regulates Adenylyl Cyclase Type 8 Mol. Pharmacol., April 1, 2009; 75(4): 830 - 842. [Abstract] [Full Text] [PDF]

				N. Masada, A. Ciruela, D. A. MacDougall, and D. M. F. Cooper Distinct Mechanisms of Regulation by Ca2+/Calmodulin of Type 1 and 8 Adenylyl Cyclases Support Their Different Physiological Roles J. Biol. Chem., February 13, 2009; 284(7): 4451 - 4463. [Abstract] [Full Text] [PDF]

				I. Gekel and E. Neher Application of an Epac Activator Enhances Neurotransmitter Release at Excitatory Central Synapses J. Neurosci., August 6, 2008; 28(32): 7991 - 8002. [Abstract] [Full Text] [PDF]

				L. E. Fridlyand, M. C. Harbeck, M. W. Roe, and L. H. Philipson Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic -cell: a computational approach Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1924 - C1933. [Abstract] [Full Text] [PDF]

				D. Willoughby and D. M. F. Cooper Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains Physiol Rev, July 1, 2007; 87(3): 965 - 1010. [Abstract] [Full Text] [PDF]

				L. N. Borodinsky and N. C. Spitzer Second Messenger Pas de Deux: The Coordinated Dance Between Calcium and cAMP Sci. Signal., May 23, 2006; 2006(336): pe22 - pe22. [Abstract] [Full Text] [PDF]