Real-time monitoring of cyclic nucleotide signaling in neurons using genetically encoded FRET probes

Signaling cascades involving cyclic nucleotides play key roles in signal transduction in virtually all cell types. Elucidation of the spatiotemporal regulation of cyclic nucleotide signaling requires methods for tracking the dynamics of cyclic nucleotides and the activities of their regulators and effectors in the native biological context. Here we review a series of genetically encoded FRET-based probes for real-time monitoring of cyclic nucleotide signaling with a particular focus on their implementation in neurons. Current data indicate that neurons have a very active metabolism in cyclic nucleotide signaling, which is tightly regulated through a variety of homeostatic regulations.

[1]  Roger Y. Tsien,et al.  Spatiotemporal dynamics of guanosine 3′,5′-cyclic monophosphate revealed by a genetically encoded, fluorescent indicator , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J. Goaillard,et al.  Simultaneous measurements of intracellular cAMP and L‐type Ca2+ current in single frog ventricular myocytes , 2001, The Journal of physiology.

[3]  Roger Y Tsien,et al.  Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes. , 2005, Nature.

[4]  Necmettin Yildirim,et al.  β2-Adrenergic Receptor Signaling and Desensitization Elucidated by Quantitative Modeling of Real Time cAMP Dynamics* , 2008, Journal of Biological Chemistry.

[5]  Ronald L. Davis,et al.  Cyclic AMP Imaging Sheds Light on PDF Signaling in Circadian Clock Neurons , 2008, Neuron.

[6]  D. Cooper,et al.  A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Victor H Hernandez,et al.  Nature Methods , 2007 .

[8]  B. Lambolez,et al.  Phosphodiesterase type 2 and the homeostasis of cyclic GMP in living thalamic neurons , 2007, Journal of neurochemistry.

[9]  Oliver Griesbeck,et al.  Improved calcium imaging in transgenic mice expressing a troponin C–based biosensor , 2007, Nature Methods.

[10]  D. Cooper,et al.  Live-cell imaging of cAMP dynamics , 2008, Nature Methods.

[11]  Stepan Gambaryan,et al.  Fluorescent sensors for rapid monitoring of intracellular cGMP , 2005, Nature Methods.

[12]  J. Changeux,et al.  Live imaging of neural structure and function by fibred fluorescence microscopy , 2006, EMBO reports.

[13]  R. Tsien,et al.  Partitioning of Lipid-Modified Monomeric GFPs into Membrane Microdomains of Live Cells , 2002, Science.

[14]  Susan S. Taylor,et al.  The catalytic subunit of cAMP-dependent protein kinase: prototype for an extended network of communication. , 1999, Progress in biophysics and molecular biology.

[15]  Xiaodong Cheng,et al.  Fluorescent indicators of cAMP and Epac activation reveal differential dynamics of cAMP signaling within discrete subcellular compartments. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[16]  B. Domingo,et al.  Imaging FRET standards by steady‐state fluorescence and lifetime methods , 2007, Microscopy research and technique.

[17]  Shigeyuki Namiki,et al.  NO signalling decodes frequency of neuronal activity and generates synapse‐specific plasticity in mouse cerebellum , 2005, The Journal of physiology.

[18]  R Y Tsien,et al.  Practical design criteria for a dynamic ratio imaging system. , 1990, Cell calcium.

[19]  Y. Umezawa,et al.  Fluorescent indicators for cyclic GMP based on cyclic GMP-dependent protein kinase Ialpha and green fluorescent proteins. , 2000, Analytical chemistry.

[20]  M. Zaccolo,et al.  Transgenic fruit-flies expressing a FRET-based sensor for in vivo imaging of cAMP dynamics. , 2007, Cellular signalling.

[21]  Sharon M. Cawley,et al.  Cygnets: in vivo characterization of novel cGMP indicators and in vivo imaging of intracellular cGMP. , 2005, Methods in molecular biology.

[22]  Roger Y. Tsien,et al.  Insulin disrupts β-adrenergic signalling to protein kinase A in adipocytes , 2005, Nature.

[23]  Kees Jalink,et al.  Detecting cAMP‐induced Epac activation by fluorescence resonance energy transfer: Epac as a novel cAMP indicator , 2004, EMBO reports.

[24]  B. Kemp.  Phosphorylation of acyl and dansyl derivatives of the peptide Leu-Arg-Arg-Ala-Ser-Leu-Gly by the cAMP-dependent protein kinase. , 1980, The Journal of biological chemistry.

[25]  U. Kaupp,et al.  Molecular diversity of pacemaker ion channels. , 2001, Annual review of physiology.

[26]  R. Pepperkok,et al.  Spectral imaging and linear un‐mixing enables improved FRET efficiency with a novel GFP2–YFP FRET pair , 2002, FEBS letters.

[27]  M. Lohse,et al.  Optical techniques to analyze real-time activation and signaling of G-protein-coupled receptors. , 2008, Trends in pharmacological sciences.

[28]  P. Taghert,et al.  Widespread Receptivity to Neuropeptide PDF throughout the Neuronal Circadian Clock Network of Drosophila Revealed by Real-Time Cyclic AMP Imaging , 2008, Neuron.

[29]  Martin J. Lohse,et al.  Novel Single Chain cAMP Sensors for Receptor-induced Signal Propagation*♦ , 2004, Journal of Biological Chemistry.

[30]  E R Kandel,et al.  Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons. , 1993, Science.

[31]  R. Tsien,et al.  A new generation of Ca2+ indicators with greatly improved fluorescence properties. , 1985, The Journal of biological chemistry.

[32]  N. Spitzer,et al.  Dynamic interactions of cyclic AMP transients and spontaneous Ca2+ spikes , 2002, Nature.

[33]  M. Lohse,et al.  Cyclic AMP Imaging in Adult Cardiac Myocytes Reveals Far-Reaching &bgr;1-Adrenergic but Locally Confined &bgr;2-Adrenergic Receptor–Mediated Signaling , 2006, Circulation research.

[34]  G. Milligan,et al.  Tailoring cAMP-signalling responses through isoform multiplicity. , 1997, Trends in biochemical sciences.

[35]  B. Lambolez,et al.  Dynamics of Protein Kinase A Signaling at the Membrane, in the Cytosol, and in the Nucleus of Neurons in Mouse Brain Slices , 2007, The Journal of Neuroscience.

[36]  Lili X. Peng,et al.  Systems analysis of PKA-mediated phosphorylation gradients in live cardiac myocytes , 2006, Proceedings of the National Academy of Sciences.

[37]  Susan S. Taylor,et al.  Fluorescence ratio imaging of cyclic AMP in single cells , 1991, Nature.

[38]  P. Vincent,et al.  Cyclic AMP imaging in neurones in brain slice preparations , 2001, Journal of Neuroscience Methods.

[39]  R Y Tsien,et al.  Genetically encoded reporters of protein kinase A activity reveal impact of substrate tethering , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Knighton,et al.  Systematic mutational analysis of cAMP-dependent protein kinase identifies unregulated catalytic subunits and defines regions important for the recognition of the regulatory subunit. , 1992, The Journal of biological chemistry.

[41]  E. Kandel,et al.  Proceedings of the National Academy of Sciences of the United States of America. Annual subject and author indexes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[42]  B. Herman,et al.  Quantitative fluorescence resonance energy transfer measurements using fluorescence microscopy. , 1998, Biophysical journal.

[43]  Yoshio Umezawa,et al.  Imaging the nanomolar range of nitric oxide with an amplifier-coupled fluorescent indicator in living cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  J. Swanson,et al.  Fluorescence resonance energy transfer-based stoichiometry in living cells. , 2002, Biophysical journal.

[45]  J. Schaack,et al.  In Vivo Assessment of Local Phosphodiesterase Activity Using Tailored Cyclic Nucleotide–Gated Channels as Camp Sensors , 2001, The Journal of general physiology.

[46]  D Zicha,et al.  Quantitative fluorescence resonance energy transfer (FRET) measurement with acceptor photobleaching and spectral unmixing , 2004, Journal of microscopy.

[47]  E. Humble,et al.  The minimum substrate of cyclic AMP-stimulated protein kinase, as studied by synthetic peptides representing the phosphorylatable site of pyruvate kinase (type L) of rat liver. , 1976, Biochemical and biophysical research communications.

[48]  M. Zaccolo,et al.  Imaging of cAMP Levels and Protein Kinase A Activity Reveals That Retinal Waves Drive Oscillations in Second-Messenger Cascades , 2006, The Journal of Neuroscience.

[49]  A. Friebe,et al.  Design of fluorescence resonance energy transfer (FRET)-based cGMP indicators: a systematic approach. , 2007, The Biochemical journal.

[50]  Allen I. Selverston,et al.  Spatio-temporal dynamics of cyclic AMP signals in an intact neural circuit , 1996, Nature.

[51]  Jin Zhang,et al.  Subcellular dynamics of protein kinase A activity visualized by FRET-based reporters. , 2006, Biochemical and biophysical research communications.

[52]  J. W. Karpen,et al.  Review Article: Cyclic AMP Sensors in Living Cells: What Signals Can They Actually Measure? , 2002, Annals of Biomedical Engineering.

[53]  A. Bonev,et al.  Differential patterning of cGMP in vascular smooth muscle cells revealed by single GFP-linked biosensors , 2008, Proceedings of the National Academy of Sciences.

[54]  Martin J. Lohse,et al.  Fluorescence Resonance Energy Transfer–Based Analysis of cAMP Dynamics in Live Neonatal Rat Cardiac Myocytes Reveals Distinct Functions of Compartmentalized Phosphodiesterases , 2004, Circulation research.

[55]  M. Zaccolo,et al.  Improvement of a FRET-based indicator for cAMP by linker design and stabilization of donor-acceptor interaction. , 2005, Journal of molecular biology.

[56]  Susan S. Taylor,et al.  A genetically encoded, fluorescent indicator for cyclic AMP in living cells , 1999, Nature Cell Biology.