The Adenosine A2A Receptor Interacts with the Actin-binding Protein α-Actinin

Burgueño, Javier; Blake, Derek J.; Benson, Matthew A.; Tinsley, Caroline L.; Esapa, Christopher T.; Canela, Enric I.; Penela, Petronila; Mallol, Josefa; Mayor, Federico; Lluı́s, Carmen; Franco, Rafael; Ciruela, Francisco

doi:10.1074/jbc.m302809200

Cited by 103 publications

(93 citation statements)

References 41 publications

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“…The mechanisms by which this effect occurs are not known; however, there is evidence that the C-terminal domain of the A 2A R interact with ␣-actinin, a major F-actincross-linking protein through co-localization, co-immunoprecipitation, and pull-down experiments. 17 Previous observation demonstrated a transient dysregulation of ␣-actinin in podocytes just before the development of foot process effacement 18 and a concomitant redistribution of ␣-actinin and actin associated with PAN-induced nephrosis. 41 In addition, ␣-actinin has been shown to bind ␤ 1 integrin subunit and strengthen the podocyte-GBM interaction, thereby stabilizing glomerular architecture.…”

Section: Discussionmentioning

confidence: 99%

“…15 It is interesting that, in these studies, diabetic kidney disease was associated with reduced podocin and nephrin mRNA expression, but their expression was restored in animals treated with A 2A R agonists. 15 A 2A R are found in glomeruli, 16 and recently A 2A R were found to associate with ␣-actinin-4, a cytoskeletal protein, 17 which when mutated is thought to lead to FSGS. 9,18 These results raise the possibility that A 2A R agonists may have a direct effect on podocytes; therefore, we sought to determine whether A 2A R agonists had direct effects on podocytes to preserve glomerular filtration barrier function.…”

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confidence: 99%

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Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes

Awad

Rouse

Liu

et al. 2008

Journal of the American Society of Nephrology

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Adenosine 2A receptor (A 2A R) activation was recently shown to be renoprotective in diabetic nephropathy. A 2A R are found in glomeruli and have been shown to associate with the podocyte cytoskeletal protein ␣-actinin-4, but the effect of their activation on podocyte structure and function is unknown. Podocyte injury was induced in C57BL/6 mice with puromycin aminonucleoside, and the selective A 2A R agonist ATL313 was found to attenuate the resulting albuminuria and foot process fusion. The selective A 2A R antagonist ZM241385 reversed the effects of ATL313. In vitro, A 2A R mRNA and protein were expressed in a conditionally immortalized podocyte cell line, and A 2A R-like immunoreactivity co-localized with the actin cytoskeleton. Treatment with ATL313 also blocked the increased podocyte permeability to albumin and disruption of the actin cytoskeleton that accompanied puromycin aminonucleosideinduced injury in vitro. ATL313 was ineffective, however, in the presence of the A 2A R antagonist and in A 2A R-deficient podocytes. It was concluded that A 2A R activation reduces glomerular proteinuria, at least in part, by preserving the normal structure of podocyte foot processes, slit diaphragms, and actin cytoskeleton.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes

Awad

Rouse

Liu

et al. 2008

Journal of the American Society of Nephrology

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“…Immobilized fusion proteins (12 g) were incubated with SR membrane or cytosolic proteins (500 g) in 1 ml of TBS (50 mM Tris, 100 mM NaCl, pH 7.4, plus 0.1% Triton X-100 with 1 mM free Ca 2ϩ ) buffer for 2 h at 4°C. The salt concentrations in the buffer used were similar to that used by others (30). Beads were washed four times in TBS.…”

Section: Methodsmentioning

confidence: 99%

The Muscle-specific Calmodulin-dependent Protein Kinase Assembles with the Glycolytic Enzyme Complex at the Sarcoplasmic Reticulum and Modulates the Activity of Glyceraldehyde-3-phosphate Dehydrogenase in a Ca2+/Calmodulin-dependent Manner

Singh

Salih

Leddy

et al. 2004

Journal of Biological Chemistry

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The skeletal muscle specific Ca 2؉ /calmodulin-dependent protein kinase (CaMKII␤ M ) is localized to the sarcoplasmic reticulum (SR) by an anchoring protein, ␣KAP, but its function remains to be defined. Protein interactions of CaMKII␤ M indicated that it exists in complex with enzymes involved in glycolysis at the SR membrane. The kinase was found to complex with glycogen phosphorylase, glycogen debranching enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and creatine kinase in the SR membrane. CaMKII␤ M was also found to assemble with aldolase A, GAPDH, enolase, lactate dehydrogenase, creatine kinase, pyruvate kinase, and phosphorylase b kinase from the cytosolic fraction. The interacting proteins were substrates of CaMKII␤ M , and their phosphorylation was enhanced in a Ca 2؉ -and calmodulin (CaM)-dependent manner. The CaMKII␤ M could directly phosphorylate GAPDH and markedly increase (ϳ3.4-fold) its activity in a Ca 2؉ /CaMdependent manner. These data suggest that the muscle CaMKII␤ M isoform may serve to assemble the glycogenmobilizing and glycolytic enzymes at the SR membrane and specifically modulate the activity of GAPDH in response to calcium signaling. Thus, the activation of CaMKII␤ M in response to calcium signaling would serve to modulate GAPDH and thereby ATP and NADH levels at the SR membrane, which in turn will regulate calcium transport processes.Free calcium (Ca 2ϩ ) regulates diverse cellular functions by acting as an intracellular second messenger. A large part of these cellular functions are mediated by CaM, 1 which is the ubiquitous intracellular Ca 2ϩ receptor. The Ca 2ϩ ⅐CaM complex allosterically activates numerous proteins, including Ca 2ϩ /CaMdependent protein kinase II (CaMKII) (1). CaMKII is a multifunctional enzyme that is highly expressed in brain and muscle. The kinase is believed to serve important roles in synaptic transmission (2, 3), gene transcription (4, 5), cell growth (6), and control of excitation-contraction coupling (7-9).The subcellular distribution of CaMKII indicates cytosolic and membrane localizations in different tissues (10). In skeletal muscle, an isoform of CaMKII is targeted to the SR membrane by a non-kinase protein, ␣KAP (11, 12). Different studies have been conducted to determine whether membrane-bound CaM kinase could phosphorylate different substrate proteins by virtue of its proximity effects and thereby regulate SR function. Although the calcium release channel/ryanodine receptor (RyR) and the calcium pump/Ca 2ϩ -ATPase in skeletal muscle SR were shown to be substrates of CaMKII␤ (13, 14), there does not appear to be any clear effects on the regulation of functional activity of these proteins induced by such phosphorylation (7,8,(15)(16)(17). Moreover, there is clear evidence that the RyR and calcium pump are regulated by local ATP, Ca 2ϩ , and CaM through direct ligand binding (15)(16)(17). In this regard, both Ca 2ϩ and CaM are present at the SR, and the level of ATP is believed to be tightly controlled through a membrane-bound glycolytic mac...

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“…Receptorinteracting proteins of GPCR as signaling complexes have been identified (Bermak and Zhou, 2001): DRiP78 for D1R, and spinophilin, filamin A, and Protein 4.1N for D2R (Binda et al, 2002). In addition, a-actinin has been reported to be an association molecule of A 2A R (Burgueño et al, 2003). However, these proteins are not type II TM proteins with a cytoplasmic N-terminal segment, single TM, and extracellular C-terminal tail.…”

Section: Resultsmentioning

confidence: 99%

Functional Expression of Single-Chain Heterodimeric G-Protein-Coupled Receptors for Adenosine and Dopamine

Kamiya

Saitoh

Nakata

2005

Cell Struct. Funct.

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ABSTRACT. The direct homo-and heteromeric association between G-protein-coupled receptors (GPCRs), adenosine A2A receptor (A2AR) and dopamine D2 receptor (D2R), occurs although little is known about the selectivity of their formation (A2AR/A2AR vs. A2AR/D2R). In order to stimulate the heteromerization of A2AR and D2R, we have designed a single-polypeptide-chain heterodimeric A2AR/D2R complex by fusing the C-terminus of the A2AR via transmembrane (TM) of a type II TM protein with the N-terminus of D2R in tandem. This was successfully expressed on the cell surface as a full-length protein with specific binding to the respective ligands and functional coupling to G-proteins comparable to wild-type receptors, suggesting the possible creation of physiologically relevant heteromeric A2AR/D2R. This expression system would be useful to exclusively clarify the properties of heteromeric GPCRs irrespective of homomeric receptors.

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The Adenosine A2A Receptor Interacts with the Actin-binding Protein α-Actinin

Cited by 103 publications

References 41 publications

Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes

Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes

The Muscle-specific Calmodulin-dependent Protein Kinase Assembles with the Glycolytic Enzyme Complex at the Sarcoplasmic Reticulum and Modulates the Activity of Glyceraldehyde-3-phosphate Dehydrogenase in a Ca2+/Calmodulin-dependent Manner

Functional Expression of Single-Chain Heterodimeric G-Protein-Coupled Receptors for Adenosine and Dopamine

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