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

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

doi:10.1007/s12104-015-9618-y

Cited by 2 publications

(2 citation statements)

References 9 publications

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“…This carboxy‐terminal is a highly dynamic domain (Tossavainen et al . ), which has not been resolved at the atomic level as the rest of the A 2A R (Jaakola et al . ; Lebon et al .…”

Section: Signaling Mechanisms Underlying A2ar‐mediated Neurodegenerationmentioning

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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“…This carboxy‐terminal is a highly dynamic domain (Tossavainen et al . ), which has not been resolved at the atomic level as the rest of the A 2A R (Jaakola et al . ; Lebon et al .…”

Section: Signaling Mechanisms Underlying A2ar‐mediated Neurodegenerationmentioning

confidence: 99%

How does adenosine control neuronal dysfunction and neurodegeneration?

Cunha

2016

Journal of Neurochemistry

378

385

View full text Add to dashboard Cite

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“…In crystallization constructs, the A 2A AR amino acid sequence was truncated at position 316 in order to facilitate crystallization. NMR studies of the isolated C-terminal polypeptide showed that it is intrinsically disordered 180,181 , and additional biophysical data suggested that this intrinsic flexibility is important for complex formation with various partner proteins, including calmodulin 180 . Intrinsically disordered polypeptide segments in GPCRs have been shown to be subject to posttranslational modifications and thought to be critical for interactions with G proteins and other partner proteins 182 .…”

Section: Nmr Studies Of Human Gpcrsmentioning

confidence: 99%

GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures

Shimada

Ueda

Kofuku

et al. 2018

Nat Rev Drug Discov

206

174

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The 826 G protein-coupled receptors (GPCRs) in the human proteome regulate key physiological processes, and thus have long been attractive as drug targets. With crystal structure determinations of more than 50 different human GPCRs during the last decade, an initial platform for structure-based rational design has been established for drugs that target GPCRs, which is currently being augmented with cryo-EM structures of higher-order GPCR complexes. Nuclear magnetic resonance (NMR) spectroscopy in solution is one of the key approaches for expanding this platform with dynamic features, which can be accessed at physiological temperature and with minimal modification of the wild-type GPCR covalent structures. Here, we review strategies for the use of advanced biochemistry and NMR techniques with GPCRs, survey projects where crystal or cryo-EM structures have been complemented with NMR investigations, and discuss the impact of this integrative approach on GPCR biology and drug discovery. More than 30% of all drugs approved by the US Food and Drug Administration target G protein-coupled receptors (GPCRs)1–3, and these drugs are utilized in a wide range of therapeutic areas, including inflammation and diseases of the central nervous system as well as the cardiovascular, respiratory and gastrointestinal systems2,4. Currently more than 300 agents are in clinical trials, of which around 60 target novel GPCRs for which no drug has as yet been approved2. The novel GPCR targets also include orphan GPCRs, for which endogenous ligands have not yet been discovered2. Overall, the drugs approved so far target only 27% of the human non-olfactory GPCRs2, indicating that much excitement still lies ahead. Identifying new GPCR drugs will need additional detailed knowledge of GPCR biology, especially knowledge from structural biology, given the complex structure–function relationships involved in GPCR signaling. Along this line, recent reviews on GPCRs have covered studies with antibodies5 and nanobodies6, allosteric modulation7–10 biased signaling11–15, methods in GPCR structural biology16–19, GPCR crystal structures20–27 and drug development2,4,28,29, with some reviews addressing specific GPCR families30,31. Complementing the substantial number of GPCR crystal structures that have become available in the past decade, as well as the recent demonstrations of the potential for cryo-EM to provide information on higher-order GPCR complexes32–36, dynamic studies of GPCRs are important for providing new insights into GPCR biology that can assist drug discovery. In this respect, nuclear magnetic resonance (NMR) spectroscopy in solution is a key tool for analysing function-related conformational equilibria in GPCRs as they relate to allosteric coupling, variable efficacies and biased signaling of GPCR ligands, which are of particular interest for their potential as drugs. Furthermore, NMR spectroscopy is also a useful tool for fragment-based lead discovery with GPCR targets. In this article, we first overview the structural biology of GPCRs ba...

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

Cited by 2 publications

References 9 publications

How does adenosine control neuronal dysfunction and neurodegeneration?

How does adenosine control neuronal dysfunction and neurodegeneration?

GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures

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