Human Adenosine A2A Receptor Binds Calmodulin with High Affinity in a Calcium-Dependent Manner

Piirainen, Henni; Hellman, Maarit; Tossavainen, Helena; Permi, Perttu; Kursula, Petri; Jaakola, Veli-Pekka

doi:10.1016/j.bpj.2014.12.036

Cited by 14 publications

(11 citation statements)

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“…Interestingly, the evidence gathered in the last 20 years clearly speaks against this dogma of A 2A R signaling only or mainly through the cAMP-PKA pathway. In different tissues and cells, A 2A R activation has been shown to recruit and to signal through a variety of transducing pathways such as MAPK, namely ERK1/2 (extracellular signal-regulated kinases), p38 or c-Jun N-terminal kinases, PI-3K (phosphoinositide 3-kinase), protein phosphatases, protein kinase C, Src (acronym for sarcoma) kinases, or peroxisome proliferator-activated receptor, as illustrated by this non-exhaustive list of studies (Gubitz et al 1996;Revan et al 1996;Sexl et al 1997;Palmer and Stiles 1999;Seidel et al 1999;Gardner and Olah 2003;Murphy et al 2003;Boucher et al 2004;Fotheringham et al 2004;Gsandtner et al 2005;Pinto-Duarte et al 2005;Yu et al 2005;Melani et al 2006Melani et al , 2009Sun et al 2006Sun et al , 2010Che et al 2007;De Ponti et al 2007;Fresco et al 2007;Charalambous et al 2008;Tikh et al 2008;Canas et al 2009a,b;Simões et al 2012;Tamura et al 2012;Ahmad et al 2013;Nayeem et al 2013;Wang et al 2014;Zeidan et al 2014;Merighi et al 2015;Piirainen et al 2015;Shang et al 2015;Zhang et al 2015;Mohamed et al 2016).…”

Section: Signaling Mechanisms Underlying a 2a R-mediated Neurodegenermentioning

confidence: 99%

How does adenosine control neuronal dysfunction and neurodegeneration?

Cunha

2016

Journal of Neurochemistry

378

385

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The adenosine modulation system mostly operates through inhibitory A 1 (A 1 R) and facilitatory A 2A receptors (A 2A R) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A 1 R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: highfrequency stimulation triggers ATP release in the 'activated' synapse, which is locally converted by ecto-nucleotidases into adenosine to selectively activate A 2A R; A 2A R switch off A 1 R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the 'activated' synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A 1 R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near-threshold and/or of short-duration, A 1 R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A 2A R, probably to bolster adaptive changes, but this heightens brain damage since A 2A R blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A 2A R, whereas astrocytic and microglia A 2A R might control the spread of damage. The A 2A R signaling mechanisms are largely unknown since A 2A R are pleiotropic, coupling to different G proteins and non-canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A 1 R preconditioning and preventing excessive A 2A R function might afford maximal neuroprotection. Keywords: A 1 receptor, A 2A receptor, astrocyte, microglia, synaptic plasticity, synaptotoxicity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Relevance of modulation systems to tune information flow in brain circuitsThe goal of understanding the flow of information in neuronal circuits has traditionally been centered in studying the key processes sustaining synaptic transmission and plasticity -i.e. the role of glutamate and glutamate receptors, as well as to a lesser extent the role of GABA and its receptors. If one considers an analogy to the experience of watching TV, this corresponds to studying how the ON/OFF button impacts all Received April 4, 2016; revised manuscript received May 23, 2016; accepted June 23, 2016. Address correspondence and reprint requests to R. A. Cunha, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. E-mail: cunharod@gmail.com Abbreviations used: A 1 R, adenosine A 1 receptor; A 2A R, adenosine A 2A receptor; ADHD, attention deficit and hyperactivity disorder; BDNF, brain-derived neurotrophi...

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Section: Signaling Mechanisms Underlying a 2a R-mediated Neurodegenermentioning

confidence: 99%

How does adenosine control neuronal dysfunction and neurodegeneration?

Cunha

2016

Journal of Neurochemistry

378

385

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“…Different biophysical techniques, including fluorescence, NMR and CD spectroscopy as well as ITC, SEC and native-PAGE, in fact, can be used to perform thorough structural and energetic characterization of the CML-peptide interaction and its Ca 2+ dependence. Such approaches have been applied for many Ca 2+ sensors, and not only in plants [ 10 , 113 , 117 , 118 , 119 , 120 , 121 ]. However, among Arabidopsis CML members the only CML-target complexes for which a detailed biochemical description has been achieved are CML19-RAD4 [ 32 ] and CML36-ACA8 [ 33 ].…”

Section: Interaction Of Cmls With Targetsmentioning

confidence: 99%

Towards Understanding Plant Calcium Signaling through Calmodulin-Like Proteins: A Biochemical and Structural Perspective

Verde

Dominici

Astegno

2018

IJMS

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Ca2+ ions play a key role in a wide variety of environmental responses and developmental processes in plants, and several protein families with Ca2+-binding domains have evolved to meet these needs, including calmodulin (CaM) and calmodulin-like proteins (CMLs). These proteins have no catalytic activity, but rather act as sensor relays that regulate downstream targets. While CaM is well-studied, CMLs remain poorly characterized at both the structural and functional levels, even if they are the largest class of Ca2+ sensors in plants. The major structural theme in CMLs consists of EF-hands, and variations in these domains are predicted to significantly contribute to the functional versatility of CMLs. Herein, we focus on recent advances in understanding the features of CMLs from biochemical and structural points of view. The analysis of the metal binding and structural properties of CMLs can provide valuable insight into how such a vast array of CML proteins can coexist, with no apparent functional redundancy, and how these proteins contribute to cellular signaling while maintaining properties that are distinct from CaM and other Ca2+ sensors. An overview of the principal techniques used to study the biochemical properties of these interesting Ca2+ sensors is also presented.

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“…Production of uniformly 13 C, 15 N labelled A 2A R C-terminal amino acids 293-412 has been described in Piirainen et al (2015). All A 2A -ct NMR spectra were measured in 95/5 % 50 mM HEPES, 250 mM NaCl, 1 mM TCEP-HCl, 5 mM CaCl 2 pH 7.…”

Section: Methods and Experimentsmentioning

confidence: 99%

“…We have recently shown that the C-terminal domain (A 2A -ct, residues 293-412 of A 2A R) is disordered and flexible (Piirainen et al 2015), and can adopt different conformations depending on its surroundings and interaction partners. We also showed that calmodulin binds to the eighth helix of A 2A R in a calcium-dependent manner.…”

Section: Biological Contextmentioning

confidence: 99%

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HN, N, Cα, Cβ and C′ assignments of the intrinsically disordered C-terminus of human adenosine A2A receptor

et al. 2015

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The C-terminus of the human adenosine A2A receptor differs from the other human adenosine receptors by its exceptional length and lack of a canonical cysteine residue. We have previously structurally characterized this C-terminal domain and its interaction with calmodulin. It was shown to be structurally disordered and flexible, and to bind calmodulin with high affinity in a calcium-dependent manner. Interaction with calmodulin takes place at the N-terminal end of the A2A C-terminal domain without major conformational changes in the latter. NMR was one of the biophysical methods used in the study. Here we present the H(N), N, C(α), C(β) and C' chemical shift assignments of the free form of the C-terminus residues 293-412, used in the NMR spectroscopic characterization of the domain.

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Human Adenosine A2A Receptor Binds Calmodulin with High Affinity in a Calcium-Dependent Manner

Cited by 14 publications

References 88 publications

How does adenosine control neuronal dysfunction and neurodegeneration?

How does adenosine control neuronal dysfunction and neurodegeneration?

Towards Understanding Plant Calcium Signaling through Calmodulin-Like Proteins: A Biochemical and Structural Perspective

HN, N, Cα, Cβ and C′ assignments of the intrinsically disordered C-terminus of human adenosine A2A receptor

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