A β
 2
 Adrenergic Receptor Signaling Complex Assembled with the Ca
 2+
 Channel Ca
 v
 1.2

Davare, Monika A.; Avdonin, Vladimir; Hall, Duane D.; Peden, Erik M.; Burette, A; Weinberg, Richard J.; Horne, Mary C.; Hoshi, Toshinori; Hell, Johannes

doi:10.1126/science.293.5527.98

Cited by 488 publications

(558 citation statements)

References 27 publications

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“…For example, it has been demonstrated that in hippocampus neurons, β 2 adrenergic receptor, calcium channels, G protein, adenyl cyclase and other proteins are co-localised [70]; however, these clusters of proteins are not recognised as partitioning into rafts. The authors conclude that "co-localisation of GPCRs with their ultimate targets in macromolecular complexes could be a general mechanism to ensure that signalling is both specific and fast" [70]. Note that due to the indirect methodologies used to reach this conclusion one cannot infer the microscopic mechanism responsible for co-localisation.…”

Section: Examples Of Observed Protein Confinementsmentioning

confidence: 99%

What do diffusion measurements tell us about membrane compartmentalisation? Emergence of the role of interprotein interactions

2008

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The techniques of diffusion analysis based on optical microscopy approaches have revealed a great diversity of the dynamic organisation of cell membranes. For a long period, two frameworks have dominated the way of representing the membrane structure: the membrane skeleton fences and the lipid raft models. Progresses in the methods of data analysis have shed light on the features and consequently the possible origin of membrane domains: Inter-protein interactions play a role in confinement. Innovative developments pushing forward the spatiotemporal resolution limits are currently emerging, which are likely to provide in the future a detailed understanding of the intimate functional dynamic organisation of the cell membrane. Keywords Membrane domain . Diffusion . Protein interaction OverviewThe main function of membranes is to generate close compartments: The cell itself (by the plasma membrane) and also the nucleus (by nuclear envelope), the Golgi apparatus, the endoplasmic reticulum, various organelles or the vesicles which are involved in transport processes. Membranes delimit these structures and allow them to have a different composition from the rest of the cell by restricting the diffusion of ions and macromolecules. The specific transport of molecules or information across the membrane is devoted to membrane proteins. Membranes are essentially composed of lipid and proteins, each of them representing about 50% in weight. Lipids are amphiphilic molecules that spontaneously form a bilayer in water. Among the variety of lipids, cholesterol has a specific place since it is particularly abundant in eukaryotic cells. Cholesterol can modify the lipid molecular order [1] and is presumed to participate in lipid micro-phase separation (rafts) [2][3][4][5].Since the structure of biological membranes is maintained by non-covalent bonds, they have first been considered as a fluid lipid bilayer in which embedded proteins are free to diffuse [6]. After the advent of this fluid mosaic model postulating a random distribution of membrane molecules [6], experimental evidence showed that the proteins and lipids are distributed heterogeneously in the membrane. For example, incomplete recoveries were systematically observed in fluorescence recovery after photobleaching (FRAP; see "Appendix 1") experiments. The first indication of the presence of micrometer-sized domains was obtained by FRAP. Yechiel and Edidin found a decrease of the mobile fraction with increasing radius of the bleaching spot ([7, 8] and see "Appendix 1").The huge diversity of lipids and proteins implies that a very large number of combinatorial interactions can occur between them [9]. Since all lipids and proteins do not J Chem Biol (2008) [14,15]. Interactions of membrane proteins with the cytoskeleton or with the glycocalyx can also affect the membrane organisation and are likely to play a confining role [16]. A significant challenge of cell biology is to characterise and to understand not only the origin but also the role of these micrometric ...

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Section: Examples Of Observed Protein Confinementsmentioning

confidence: 99%

What do diffusion measurements tell us about membrane compartmentalisation? Emergence of the role of interprotein interactions

2008

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“…To rule out the possibility of GST having a role in multimerization, PDZ1 was cleaved from GST by using (10) and is likely to be in the complex. On agonist activation of the receptor, adenylate cyclase is stimulated through the Gs pathway (33), leading to an increase in highly compartmentalized cAMP. This increased local concentration of cAMP leads to the activation of PKA, which is in close proximity to CFTR (36), leading to a compartmentalized and specific signaling of the channel.…”

Section: Fig 3 Macromolecular Complex Of Cftr and ␤2ar Is Mediated mentioning

confidence: 99%

A macromolecular complex of β ₂ adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA

Naren

Cobb

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

207

223

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It has been demonstrated previously that both the cystic fibrosis transmembrane conductance regulator (CFTR) and ␤2 adrenergic receptor (␤2AR) can bind ezrin͞radixin͞moesin-binding phosphoprotein 50 (EBP50, also referred to as NHERF) through their PDZ motifs. Here, we show that ␤2 is the major adrenergic receptor isoform expressed in airway epithelia and that it colocalizes with CFTR at the apical membrane. ␤2AR stimulation increases CFTR activity, in airway epithelial cells, that is glybenclamide sensitive. Deletion of the PDZ motif from CFTR uncouples the channel from the receptor both physically and functionally. This uncoupling is specific to the ␤2AR receptor and does not affect CFTR coupling to other receptors (e.g., adenosine receptor pathway). Biochemical studies demonstrate the existence of a macromolecular complex involving CFTR-EBP50-␤ 2AR through PDZ-based interactions. Assembly of the complex is regulated by PKA-dependent phosphorylation. Deleting the regulatory domain of CFTR abolishes PKA regulation of complex assembly. This report summarizes a macromolecular signaling complex involving CFTR, the implications of which may be relevant to CFTR-dysfunction diseases.

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“…Synaptic stimulation under these conditions should not enhance depolarization so it is unclear why synaptic stimulation is necessary. Recent results show that L-type VDCC in hippocampal neurons can be strongly upregulated by norepinephrine (Davare et al, 2001). One possibility is that synaptic stimulation led to the release of norepinephrine, and thereby enhanced Ca 2ϩ entry through VDCC.…”

Section: What Is the Role Of Vdcc In Ltp?mentioning

confidence: 99%

A large sustained Ca²⁺ elevation occurs in unstimulated spines during the LTP pairing protocol but does not change synaptic strength

Conti

Lisman

2002

Hippocampus

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ABSTRACT:Synapses in the CA1 region of the hippocampus undergo bidirectional synaptic modification in response to different patterns of activity. Postsynaptic Ca 2؉ elevation can trigger either synaptic strengthening or weakening, depending on the properties of the local Ca 2؉ signal. During the pairing protocol for long-term potentiation (LTP) induction, the cell is depolarized under voltage-clamp and is given low-frequency synaptic stimulation. As an initial step toward understanding the Ca 2؉ dynamics during this process, we used confocal microscopy to study the Ca 2؉ signals in spines evoked by the depolarization itself. This depolarization activates voltage-dependent Ca 2؉ channels (VDCC), but whether these channels inactivate rapidly or remain functional throughout the long depolarizations used in the pairing protocol remains unknown. Cells were depolarized to 0 mV for 2-3 min. This depolarization led to a large initial elevation of Ca 2؉ in spines that never decayed back to resting levels. The maintained signal was close to the K d of the low-affinity (5 M) Ca 2؉ dye, Magnesium Green. We attempted to determine the functional role of this elevation, using the Ca 2؉ -channel blocker D-890. The addition of D-890 in the internal solution produced a nearly complete abolition of the Ca 2؉ elevation during depolarization. Under these conditions, the NMDA conductance was normal, but LTP was almost completely blocked. This might suggest the importance of VDCC in LTP; however, we found that high concentrations of D-890 can directly inhibit calmodulin protein kinase II (CaMKII), an enzyme required for LTP induction. Thus, whereas D-890 is a useful tool for blocking postsynaptic VDCC, it cannot be used to study the contribution of these channels to plasticity. We conclude that the activation of VDCC produces a large and persistent elevation of Ca 2؉ in all spines, but does not produce either LTP or long-term depression (LTD) in the absence of synaptic stimulation. The possible reasons for this are discussed. Hippocampus 2002;12:667-679.

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A β ₂ Adrenergic Receptor Signaling Complex Assembled with the Ca ²⁺ Channel Ca _v 1.2

Cited by 488 publications

References 27 publications

What do diffusion measurements tell us about membrane compartmentalisation? Emergence of the role of interprotein interactions

What do diffusion measurements tell us about membrane compartmentalisation? Emergence of the role of interprotein interactions

A macromolecular complex of β ₂ adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA

A large sustained Ca²⁺ elevation occurs in unstimulated spines during the LTP pairing protocol but does not change synaptic strength

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A β 2 Adrenergic Receptor Signaling Complex Assembled with the Ca 2+ Channel Ca v 1.2

Cited by 488 publications

References 27 publications

What do diffusion measurements tell us about membrane compartmentalisation? Emergence of the role of interprotein interactions

What do diffusion measurements tell us about membrane compartmentalisation? Emergence of the role of interprotein interactions

A macromolecular complex of β 2 adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA

A large sustained Ca2+ elevation occurs in unstimulated spines during the LTP pairing protocol but does not change synaptic strength

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A β ₂ Adrenergic Receptor Signaling Complex Assembled with the Ca ²⁺ Channel Ca _v 1.2

A macromolecular complex of β ₂ adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA

A large sustained Ca²⁺ elevation occurs in unstimulated spines during the LTP pairing protocol but does not change synaptic strength