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Science 293 (5527): 98-101

Copyright © 2001 by the American Association for the Advancement of Science

A beta 2 Adrenergic Receptor Signaling Complex Assembled with the Ca2+ Channel Cav1.2

Monika A. Davare,1* Vladimir Avdonin,2 Duane D. Hall,1dagger Erik M. Peden,1 Alain Burette,3 Richard J. Weinberg,3 Mary C. Horne,1dagger Toshinori Hoshi,2 Johannes W. Hell1*dagger ddagger

The existence of a large number of receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) raises the question of how a particular receptor selectively regulates specific targets. We provide insight into this question by identifying a prototypical macromolecular signaling complex. The beta 2 adrenergic receptor was found to be directly associated with one of its ultimate effectors, the class C L-type calcium channel Cav1.2. This complex also contained a G protein, an adenylyl cyclase, cyclic adenosine monophosphate-dependent protein kinase, and the counterbalancing phosphatase PP2A. Our electrophysiological recordings from hippocampal neurons demonstrate highly localized signal transduction from the receptor to the channel. The assembly of this signaling complex provides a mechanism that ensures specific and rapid signaling by a G protein-coupled receptor.

1 Department of Pharmacology, University of Wisconsin, Madison, WI 53706, USA.
2 Department of Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA.
3 Department of Cell Biology and Anatomy, University of North Carolina, Chapel Hill, NC 27599, USA.
*   Present address: Vollum Institute, Oregon Health Sciences University, Portland, OR 97201, USA.

dagger    Present address: Department of Pharmacology, University of Iowa, Iowa, City, IA 52242, USA.

ddagger    To whom correspondence should be addressed. E-mail: johannes-hell{at}

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J. M. Nerbonne and R. S. Kass (2005)
Physiol Rev 85, 1205-1253
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Crosstalk of {beta}-Adrenergic Receptor Subtypes Through Gi Blunts {beta}-Adrenergic Stimulation of L-Type Ca2+ Channels in Canine Heart Failure.
J.-Q. He, R. C. Balijepalli, R. A. Haworth, and T. J. Kamp (2005)
Circ. Res. 97, 566-573
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Proliferative Signaling by Store-Operated Calcium Channels Opposes Colon Cancer Cell Cytostasis Induced by Bacterial Enterotoxins.
S. Kazerounian, G. M. Pitari, F. J. Shah, G. S. Frick, M. Madesh, I. Ruiz-Stewart, S. Schulz, G. Hajnoczky, and S. A. Waldman (2005)
J. Pharmacol. Exp. Ther. 314, 1013-1022
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Association/Dissociation of a Channel-Kinase Complex Underlies State-Dependent Modulation.
N. S. Magoski and L. K. Kaczmarek (2005)
J. Neurosci. 25, 8037-8047
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Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor-Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy.
F. Li, V. R. Drel, C. Szabo, M. J. Stevens, and I. G. Obrosova (2005)
Diabetes 54, 1514-1522
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Cyclic AMP mediates keratinocyte directional migration in an electric field.
C. E. Pullar and R. R. Isseroff (2005)
J. Cell Sci. 118, 2023-2034
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Calcium-Stimulated Adenylyl Cyclases Are Critical Modulators of Neuronal Ethanol Sensitivity.
J. W. Maas Jr, S. K. Vogt, G. C. K. Chan, V. V. Pineda, D. R. Storm, and L. J. Muglia (2005)
J. Neurosci. 25, 4118-4126
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Phosphodiesterase 4D Forms a cAMP Diffusion Barrier at the Apical Membrane of the Airway Epithelium.
A. P. Barnes, G. Livera, P. Huang, C. Sun, W. K. O'Neal, M. Conti, M. J. Stutts, and S. L. Milgram (2005)
J. Biol. Chem. 280, 7997-8003
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The Cytosolic Domains of Ca2+-sensitive Adenylyl Cyclases Dictate Their Targeting to Plasma Membrane Lipid Rafts.
A. J. Crossthwaite, T. Seebacher, N. Masada, A. Ciruela, K. Dufraux, J. E. Schultz, and D. M. F. Cooper (2005)
J. Biol. Chem. 280, 6380-6391
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A Protein Phosphatase 2c{alpha}-Ca2+ Channel Complex for Dephosphorylation of Neuronal Ca2+ Channels Phosphorylated by Protein Kinase C.
D. Li, F. Wang, M. Lai, Y. Chen, and J.-f. Zhang (2005)
J. Neurosci. 25, 1914-1923
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Using models of the myocyte for functional interpretation of cardiac proteomic data.
R. L Winslow, S. Cortassa, and J. L Greenstein (2005)
J. Physiol. 563, 73-81
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G-Protein-Coupled Receptor Modulation of Striatal CaV1.3 L-Type Ca2+ Channels Is Dependent on a Shank-Binding Domain.
P. A. Olson, T. Tkatch, S. Hernandez-Lopez, S. Ulrich, E. Ilijic, E. Mugnaini, H. Zhang, I. Bezprozvanny, and D. J. Surmeier (2005)
J. Neurosci. 25, 1050-1062
   Abstract »    Full Text »    PDF »
Phosphodiesterase 4D is required for {beta}2 adrenoceptor subtype-specific signaling in cardiac myocytes.
Y. Xiang, F. Naro, M. Zoudilova, S.-L. C. Jin, M. Conti, and B. Kobilka (2005)
PNAS 102, 909-914
   Abstract »    Full Text »    PDF »
Ser1928 Is a Common Site for Cav1.2 Phosphorylation by Protein Kinase C Isoforms.
L. Yang, G. Liu, S. I. Zakharov, J. P. Morrow, V. O. Rybin, S. F. Steinberg, and S. O. Marx (2005)
J. Biol. Chem. 280, 207-214
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Studying multiprotein complexes by multisignal sedimentation velocity analytical ultracentrifugation.
A. Balbo, K. H. Minor, C. A. Velikovsky, R. A. Mariuzza, C. B. Peterson, and P. Schuck (2005)
PNAS 102, 81-86
   Abstract »    Full Text »    PDF »
CELL BIOLOGY: Oxygen Sensing: It's a Gas!.
T. Hoshi and S. Lahiri (2004)
Science 306, 2050-2051
   Abstract »    Full Text »    PDF »
Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes: AN IN VIVO STUDY USING ADENOVIRUS-MEDIATED EXPRESSION OF CNG CHANNELS.
F. Rochais, G. Vandecasteele, F. Lefebvre, C. Lugnier, H. Lum, J.-L. Mazet, D. M. F. Cooper, and R. Fischmeister (2004)
J. Biol. Chem. 279, 52095-52105
   Abstract »    Full Text »    PDF »
The Ongoing Journey to Understand Heart Function Through Integrative Modeling.
R. L. Winslow and J. L. Greenstein (2004)
Circ. Res. 95, 1135-1136
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