嘌呤信号:中医药研究新靶点

嘌呤信号主要包括三磷酸腺苷(Adenosine Triphosphate,ATP)、二磷酸腺苷(Adenosine Diphosphate,ADP)、一磷酸腺苷(Adenosine Monophosphate,AMP)和腺苷(Adenosine,ADO)4类物质、CD39和CD73两种酶以及19种嘌呤受体(P1、P2X、P2Y),与机体各个系统均有密切关系。本文主要指出目前嘌呤信号的研究重点和中医药的未来结合靶点。

嘌呤信号与针灸镇痛

疼痛是针灸的优势适应症。解析针灸镇痛的机制是一个具有理论和现实意义的重要挑战。继Geoffrey Burnstock提出嘌呤信号参与针灸镇痛的假说以及Maiken Nedergaard证实穴位局部腺苷受体介导针刺镇痛之后,嘌呤信号成为近年来针灸镇痛的研究热点。因此,本文将对嘌呤信号与针灸镇痛的系列研究进行总结以及展望。

嘌呤信号通路对成熟神经祖细胞功能的调节

细胞外的嘌呤是胚胎发育过程中脑和脊髓原位内的信号分子,它们通过激活胚胎神经干细胞(NSCs)及成熟神经祖细胞(NPCs)表面的嘌呤受体发挥作用。虽然NSCs/NPCs内表达了能和几乎所有核苷酸敏感型P2X/P2Y受体和核酸敏感型腺苷受体相作用的m RNA和蛋白,但其中只有一部分具有功能。ATP被异位核苷酸酶依次降解为ADP,AMP和腺苷,它们都是神经激动剂并作用于不同类型的受体。核苷酸/核苷促进或抑制NSC/NPC增殖、迁移和分化。所有激动剂(特别是ATP和ADP)的最普遍的作用是促进细胞增殖,常通过P2Y1Rs,有时也通过P2X7Rs。但P2X7R的激活通常导致NPCs的坏死或凋亡。激活P2Y2R或阻断P2X7R可促进神经细胞的分化。转导机制的核心是细胞内游离钙离子浓度的升高,游离的钙离子可能来自细胞内的释放(G蛋白偶联;P2Y),或细胞外的钙离子通过被激活的受体通道进入细胞内(ATP门控离子通道;P2X)。进一步的研究将着重阐明嘌呤信号通道如何调控NSC/NPC的分化,以及静息和活化状态之间的平衡如何通过精细和动态的调节来建立。

P2X receptors in maintenance and differentiation of neural progenitor cells

Purinergic receptors are among the first cell surface receptors expressed during embryonic development （Burnstock and Ulrich, 2011）. These are characterized based on their pharmacological properties of being activated by adenosine or purine/pyrimidine nucleotides as P1 and P2 receptors. P2 receptors are further classified by their structure as P2Y metabotropic and P2X ionotropic receptors.

Regulation of neural stem/progenitor cell functions by P2X and P2Y receptors

Neural stem/progenitor cells：Radial glial cells constitute multipotent cells in the ventricular zone,lining the wall of the lateral ventricle of the embryonic brain.They have the capacity to give rise to cells belonging to all three major linages（neurons,astrocytes and oligodendrocytes）of the nervous system（Tang and Illes,2017）.

Prefrontocortical Astrocytes Regulate Dominance Hierarchy in Male Mice

Social hierarchy is a general self-organizational scheme in animal societies in which each member achieves a certain status of domination or subordination when getting access to resources,with profound consequences for survival,health,reproductive success,and multiple behaviors[1,2].The prefrontal cortex(PFC)was recognized as a central regulator of neuronal circuits determining the formation of social hierarchy;brain areas upstream of the PFC convey information about social status,and downstream brain regions execute dominance behavior[3].Social deficits have been suggested to be due to an elevation of excitatory/inhibitory(E/l)balance within the mouse dorsomedial(dm)PFC[4].A compensatory increase of inhibitory cell excitability partially rescued social deficits caused by such a disturbance of E/l balance.

Astrocytes in human central nervous system diseases: a frontier for new therapies

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system(CNS).Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome.Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions.Astroglia respond to external,non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure,molecular expression,and function.In addition,internally driven,cell autonomous changes of astroglial innate properties can lead to CNS pathologies.Astroglial pathophysiology is complex,with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder,disorder-stage,comorbidities,age,and sex.Here,we classify astroglial pathophysiology into(i)reactive astrogliosis,(ii)astroglial atrophy with loss of function,(iii)astroglial degeneration and death,and(iv)astrocytopathies characterised by aberrant forms that drive disease.We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders,including neurotrauma,stroke,neuroinfection,autoimmune attack and epilepsy,as well as neurodevelopmental,neurodegenerative,metabolic and neuropsychiatric disorders.Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.

Purinergic Receptors in Basal Ganglia Diseases:Shared Molecular Mechanisms between Huntington’s and Parkinson’s Disease

Huntington’s(HD)and Parkinson’s diseases(PD)are neurodegenerative disorders caused by the death of GABAergic and dopaminergic neurons in the basal ganglia leading to hyperkinetic and hypokinetic symptoms,respectively.We review here the participation of purinergic receptors through intracellular Ca^2+signaling in these neurodegenerative diseases.The adenosine A2A receptor stimulates striatopallidal GABAergic neurons,resulting in inhibitory actions on GABAergic neurons of the globus pallidus.A2A and dopamine D2 receptors form functional heteromeric complexes inducing allosteric inhibition,and A2A receptor activation results in motor inhibition.Furthermore,the A2A receptor physically and functionally interacts with glutamate receptors,mainly with the mGlu5 receptor subtype.This interaction facilitates glutamate release,resulting in NMDA glutamate receptor activation and an increase of Ca2+influx.P2X7 receptor activation also promotes glutamate release and neuronal damage.Thus,modulation of purinergic receptor activity,such as A2A and P2X7 receptors,and subsequent aberrant Ca^2+signaling,might present interesting therapeutic potential for HD and PD.

From purines to purinergic signalling:molecular functions and human diseases

Purines and their derivatives,most notably adenosine and ATP,are the key molecules controlling intracellular energy homoeostasis and nucleotide synthesis.Besides,these purines support,as chemical messengers,purinergic transmission throughout tissues and species.Purines act as endogenous ligands that bind to and activate plasmalemmal purinoceptors,which mediate extracellular communication referred to as“purinergic signalling”.Purinergic signalling is cross-linked with other transmitter networks to coordinate numerous aspects of cell behaviour such as proliferation,differentiation,migration,apoptosis and other physiological processes critical for the proper function of organisms.Pathological deregulation of purinergic signalling contributes to various diseases including neurodegeneration,rheumatic immune diseases,inflammation,and cancer.Particularly,gout is one of the most prevalent purine-related disease caused by purine metabolism disorder and consequent hyperuricemia.Compelling evidence indicates that purinoceptors are potential therapeutic targets,with specific purinergic agonists and antagonists demonstrating prominent therapeutic potential.Furthermore,dietary and herbal interventions help to restore and balance purine metabolism,thus addressing the importance of a healthy lifestyle in the prevention and relief of human disorders.Profound understanding of molecular mechanisms of purinergic signalling provides new and exciting insights into the treatment of human diseases.

Impaired ATP Release from Brain Astrocytes May be a Cause of Major Depression

Major depressive disease(MDD)is one of the most common mental disorders and a leading cause of disability[1].Core symptoms include depressed mood,increased apathy,and a general loss of interest.In consequence,it represents not only a personal hardship for the patients themselves,but also a major socio-economic burden for society as a whole.

Purinergic Signaling in the Central Nervous System in Health and Disease

The existence of purinergic signaling—the idea that almost all cells of the animal/human organism are able to communicate with each other via extracellular purines—was proposed by Geoffrey Burnstock(1929-2020)in 1972[1-3].The purinergic system includes the following constituents:(1)the four main purines:adenosine triphosphate(ATP)and its metabolites,adenosine diphosphate(ADP),adenosine monophosphate(AMP),and adenosine(ADO);(2)three key enzymes,the ectonucleoside triphosphate diphosphohydrolases(E-NTPDases:NTPDase1/CD39),ectonucleotide pyrophosphatase/phosphodiesterases(E-NPP),and ecto-5’-nucleotidase(E-5’-nucleotidase/CD73),which decompose ATP into ADP,AMP,and ADO.

Astrocyte-derived ATP:A New Etiological Factor for Autism Spectrum Disorder

In the central nervous system,purinergic signaling plays an important role in maintaining the functions of neurons,astrocytes,and microglia,thereby regulating brain homeostasis,with consequences for higher-order cognitive processes[1].ATP released from astrocytes in conjunction with several additional signaling molecules modulates neuronal circuits.

TASK-3:New Target for Pain-Relief

Morphine and other opioids are among the most effective analgesics for treating pain.However,drug dependence and other deleterious side effects of opioids have limited their clinical applicability.Recent studies suggest that the use of opioids for pain control may even exacerbate disease outcomes in some pain-producing conditions,such as acute pancreatitis[1].

Glial-neuronal Sensory Organs:Evolutionary Journey from Caenorhabditis elegans to Mammals

Recently,a paper published in Science reported discovery of sensory peripheral glial cells[1].This paper demonstrated a rather unexpected property of non-myelinating Schwann cells(also known as Remak cells)dwelling in the subepidermal border of the skin[2].These glial cells and their interactions with nociceptive nerve terminals were characterized using a variety of genetic labelling tools,transmission electron microscopy,immunocytochemistry.

Surveilling microglia dampens neuronal activity:operation of a purinergically mediated negative feedback mechanism

The recent paper published in Nature by Badimon et al.demonstrates that neuronal activity via the stimulation of surveilling microglia feeds back to inhibit neuronal networks.1 This effect is mediated by the release of ATP from the terminals of excitatory neurons;subsequently,ATP is degraded to adenosine by microglial enzymes,imposing an inhibitory,A1 receptor(R)-mediated control on the hyperactive neurons themselves.

The anti-inflammatory astrocyte revealed:the role of the microbiome in shaping brain defences

The paper,published recently in Nature by the group of Francisco Quintana,1 describes the anti-inflammatory astrocytes,activity of which is tuned by the microbiotome and meningeal natural killer(NK)cells.Astrocytes are a sub-type of neuroglia responsible for homoeostasis and defence of the nervous system.Pathological reactions of neuroglial cells in various neurological disorders have been identified and characterised in the end of the 19th century;in particular hypertrophy of astrocytes was recognised as a frequent morbid change accompanying diseases of the central nervous system(CNS).