Go It Alone No More—P2X7 Joins the Society of Heteromeric ATP-Gated Receptor Channels

Dubyak, George R.

doi:10.1124/mol.107.042077

Cited by 78 publications

(74 citation statements)

References 38 publications

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“…This is in agreement with previous hypothesis suggesting their origin from gene duplication [56]. Their joint evolution can be driven by the selective pressure generated by their functional role in the central nervous system, where these two subunits are mainly responsible for the activation of the inflammasome after injury [57].…”

Section: Discussionsupporting

confidence: 80%

Genomic Organization of Purinergic P2X Receptors

Loera-Valencia¹,

Jaramillo-Polanco²,

Liñán-Rico³

et al. 2015

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Purinergic P2X receptors are a family of ligand-gated cationic channels activated by extracellular ATP. P2X subunit protein sequences are highly conserved between vertebrate species. However, they can generate a great diversity of coding splicing variants to fulfill several roles in mammalian physiology. Despite intensive research in P2X expression in both central and peripheral nervous system, there is little information about their homology, genomic structure and other key features that can help to develop selective drugs or regulatory strategies of pharmacological value which are lacking today. In order to obtain clues on mammalian P2X diversity, we have performed a bioinformatics analysis of the coding regions and introns of the seven P2X subunits present in human, simian, dog, mouse, rat and zebrafish. Here we report the arrangements of exon and intron sequences, considering its number, size, phase and placement; proposing some ideas about the gain and loss of exons and retention of introns. Taken together, these evidences show traits that can be used to gain insight into the evolutionary history of vertebrate P2X receptors and better understand the diversity of subunits coding the purinergic signaling in mammals.

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Section: Discussionsupporting

confidence: 80%

Genomic Organization of Purinergic P2X Receptors

Loera-Valencia¹,

Jaramillo-Polanco²,

Liñán-Rico³

et al. 2015

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“…Until recently P2X 7 receptors were the only P2X isoform thought not to form a heteromeric channel. However, recent reports have identified P2X 4 /P2X 7 heteromeric channels (29,30). These latter observations suggest that salivary gland cells might contain both P2X 4 and P2X 7 homotrimers, as well as P2X 4 /P2X 7 heterotrimers.…”

Section: Discussionmentioning

confidence: 71%

Purinergic P2X7 Receptors Mediate ATP-induced Saliva Secretion by the Mouse Submandibular Gland

Nakamoto

Brown

Catalán

et al. 2009

Journal of Biological Chemistry

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Salivary glands express multiple isoforms of P2X and P2Y nucleotide receptors, but their in vivo physiological roles are unclear. P2 receptor agonists induced salivation in an ex vivo submandibular gland preparation. The nucleotide selectivity sequence of the secretion response was BzATP Ͼ Ͼ ATP > ADP Ͼ Ͼ UTP, and removal of external Ca 2؉ dramatically suppressed the initial ATP-induced fluid secretion (ϳ85%). Together, these results suggested that P2X receptors are the major purinergic receptor subfamily involved in the fluid secretion process. Mice with targeted disruption of the P2X 7 gene were used to evaluate the role of the P2X 7 receptor in nucleotide-evoked fluid secretion. P2X 7 receptor protein and BzATPactivated inward cation currents were absent, and importantly, purinergic receptor agonist-stimulated salivation was suppressed by more than 70% in submandibular glands from P2X 7 -null mice. Consistent with these observations, the ATP-induced increases in [Ca 2؉ ] i were nearly abolished in P2X 7 ؊/؊ submandibular acinar and duct cells. ATP appeared to also act through the P2X 7 receptor to inhibit muscarinic-induced fluid secretion. These results demonstrate that the ATP-sensitive P2X 7 receptor regulates fluid secretion in the mouse submandibular gland.Salivation is a Ca 2ϩ -dependent process (1, 2) primarily associated with the neurotransmitters norepinephrine and acetylcholine, release of which stimulates ␣-adrenergic and muscarinic receptors, respectively. Both types of receptors are coupled to G proteins that activate phospholipase C␤ (PLC␤) during salivary gland stimulation. PLC␤ activation cleaves phosphatidylinositol 1,4-bisphosphate resulting in diacylglycerol and inositol 1,4,5-trisphosphate (InsP 3 ) production. Activation of Ca 2ϩ -selective InsP 3 receptor channels localized to the endoplasmic reticulum of salivary acinar cells increases the intracellular free calcium concentration ([Ca 2ϩ ] i ). 4 Depletion of the endoplasmic reticulum Ca 2ϩ pool triggers extracellular Ca 2ϩ influx and a sustained elevation in [Ca 2ϩ ] i . This increase in [Ca 2ϩ ] i activates Ca 2ϩ -dependent K ϩ and Cl Ϫ channels promoting Cl Ϫ secretion across the apical membrane and a lumen negative, electrochemical gradient that supports Na ϩ efflux into the lumen. The accumulation of NaCl creates an osmotic gradient which drives water movement into the lumen, thus generating isotonic primary saliva. This primary fluid is then modified by the ductal system, which reabsorbs NaCl and secretes KHCO 3 producing a final saliva that is hypotonic (1, 2).Salivation also has a non-cholinergic, non-adrenergic component, the origin of which is unclear (3). In addition to muscarinic and ␣-adrenergic receptors, salivary acinar cells express other receptors that are coupled to an increase in [Ca 2ϩ ] i such as purinergic P2 and substance P receptors. Like muscarinic and ␣-adrenergic receptors, P2 receptor activation leads to a sustained increase in [Ca 2ϩ ] i in salivary acinar cells (4). In contrast, substance P receptor ac...

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“…The next major challenges are to determine the significance of this convergence in signaling for microglia function and how the upstream, as well as, downstream components contribute to aberrant spinal nociceptive processing following nerve injury. In addition to converging signaling pathways, P2 receptor subtypes can interact at the structural level to form unique receptor complexes possessing distinct biophysical properties (Dubyak, 2007;Guo et al, 2007;Jarvis and Khakh, 2009;Nicke, 2008). The potential functional consequences of this physical interaction add another layer of complexity that may have important implications for microglial P2 receptors in neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

ATP receptors gate microglia signaling in neuropathic pain

Trang

Beggs

Salter

2012

Experimental Neurology

138

104

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Microglia were described by Pio del Rio-Hortega (1932) as being the 'third element' distinct from neurons and astrocytes. Decades after this observation, the function and even the very existence of microglia as a distinct cell type was a topic of intense debate and conjecture. However, considerable advances have been made towards understanding the neurobiology of microglia resulting in a radical shift in our view of them as being passive bystanders that have solely immune and supportive roles, to being active principal players that contribute to central nervous system pathologies caused by disease or following injury. Converging lines of evidence implicate microglia as being essential in the pathogenesis of neuropathic pain, a debilitating chronic pain condition that can occur after peripheral nerve damage caused by disease, infection, or physical injury. A key molecule that modulates microglial activity is ATP, an endogenous ligand of the P2-purinoceptor family consisting of P2X ionotropic and P2Y metabotropic receptors. Microglia express several P2 receptor subtypes, and of these the P2X4, P2X7, and P2Y12 receptor subtypes have been implicated in neuropathic pain. The P2X4 receptor has emerged as the core microglianeuron signaling pathway: activation of this receptor causes release of brain-derived neurotrophic factor (BDNF) which causes disinhibition of pain-transmission neurons in spinal lamina I. The present review highlights recent advances in understanding the signaling and regulation of P2 receptors expressed in microglia and the implications for microglia-neuron interactions for the management of neuropathic pain. KeywordsMicroglia; P2 purinoceptors; Neuropathic pain; Nerve injury; ATP; BDNF; spinal cord Pain is a double-edged sword that can be protective or cause considerable suffering. Acute nociceptive pain warns against imminent or existing tissue damage, whereas chronic pain has no known defensive or beneficial function and is unremitting for those who suffer from this condition. Acute pain is produced by physiological functioning of the normal peripheral and central nervous systems. However, the processes initiated during acute pain can sometimes progress to chronic pain that is characterized as persisting long after the initiating event has healed. This transition to chronicity is highly variable between individuals and the degree of injury is not necessarily predictive of the severity or chronicity of the pain. There is mounting evidence that the transition from acute to chronic pain involves discrete CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript pathophysiological steps that alter the cellular, molecular, and anatomical organization of nociceptive neural networks in the spinal dorsal horn (Latremoliere and Woolf, 2009;Scholz and Woolf, 2002;Voscopoulos and Lema, 2010;Woolf and Salter, 2000). In this pathologically altered system, the balance of inhibitory and excitatory control is shifted such that inhibitory mechanisms are weakened while excitatory mechanisms ar...

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Go It Alone No More—P2X7 Joins the Society of Heteromeric ATP-Gated Receptor Channels

Cited by 78 publications

References 38 publications

Genomic Organization of Purinergic P2X Receptors

Genomic Organization of Purinergic P2X Receptors

Purinergic P2X7 Receptors Mediate ATP-induced Saliva Secretion by the Mouse Submandibular Gland

ATP receptors gate microglia signaling in neuropathic pain

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