Endothelin (ET)-1-Induced Inhibition of ATP Release from PC-12 Cells Is Mediated by the ET<sub>B</sub>Receptor: Differential Response to ET-1 on ATP, Neuropeptide Y, and Dopamine Levels

Gardner, Alice; Westfall, Thomas C.; Macarthur, Heather

doi:10.1124/jpet.104.081075

Cited by 13 publications

(14 citation statements)

References 37 publications

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“…In fact, these cells are known to express purinergic P2X receptors (Arthur et al, 2007), store ATP and catecholamines in dense-core vesicles (Fabbro et al, 2004), express E-NTPDase1/CD39 (Vollmayer et al, 2001), and release ATP and dopamine upon depolarization (Gardner et al, 2005). As observed before by others (Avidor et al, 1994), we noted that ATP and dopamine exocytosis in differentiated PC12 cells depends on Ca 2ϩ entry via voltage-gated Ca 2ϩ channels, particularly of the L-type.…”

Section: Discussionsupporting

confidence: 57%

The Expression Level of Ecto-NTP Diphosphohydrolase1/CD39 Modulates Exocytotic and Ischemic Release of Neurotransmitters in a Cellular Model of Sympathetic Neurons

Corti¹,

Olson²,

Marcus³

et al. 2011

J Pharmacol Exp Ther

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Once released, norepinephrine is removed from cardiac synapses via reuptake into sympathetic nerves, whereas transmitter ATP is catabolized by ecto-NTP diphosphohydrolase 1 (ENTPDase1)/CD39, an ecto-ATPase. Because ATP is known to modulate neurotransmitter release at prejunctional sites, we questioned whether this action may be ultimately controlled by the expression of E-NTPDase1/CD39 at sympathetic nerve terminals. Accordingly, we silenced E-NTPDase1/CD39 expression in nerve growth factor-differentiated PC12 cells, a cellular model of sympathetic neuron, in which dopamine is the predominant catecholamine. We report that E-NTPDase1/CD39 deletion markedly increases depolarization-induced exocytosis of ATP and dopamine and increases ATP-induced dopamine release. Moreover, overexpression of E-NTPDase1/CD39 resulted in enhanced removal of exogenous ATP, a marked decrease in exocytosis of ATP and dopamine, and a large decrease in ATP-induced dopamine release. Administration of a recombinant form of E-NTPDase1/CD39 reproduced the effects of E-NTPDase1/CD39 overexpression. Exposure of PC12 cells to simulated ischemia elicited a release of ATP and dopamine that was markedly increased in E-NTPDase1/CD39-silenced cells and decreased in E-NTPDase1/CD39-overexpressing cells. Therefore, transmitter ATP acts in an autocrine manner to promote its own release and that of dopamine, an action that is controlled by the level of E-NTPDase1/CD39 expression. Because ATP availability greatly increases in myocardial ischemia, recombinant E-NTPDase1/CD39 therapeutically used may offer a novel approach to reduce cardiac dysfunctions caused by excessive catecholamine release.

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Section: Discussionsupporting

confidence: 57%

The Expression Level of Ecto-NTP Diphosphohydrolase1/CD39 Modulates Exocytotic and Ischemic Release of Neurotransmitters in a Cellular Model of Sympathetic Neurons

Corti¹,

Olson²,

Marcus³

et al. 2011

J Pharmacol Exp Ther

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“…There was enhancement of cellular ATP levels in PC12 cells by 2,5-dideoxyadenosine, a Psite inhibitor of adenylate cyclase [716]. Endothelin-1 inhibited the release of ATP from PC12 cells via ET B receptors by attenuation of the influx of extracellular Ca 2+ through L-type channels [717]. β-Nicotinamide adenine dinucleotide was released together with ATP and DA from PC12 cells, but probably with different sites of vesicular release [718].…”

Section: Phaeochromocytomamentioning

confidence: 91%

Purinergic signalling and cancer

Burnstock

Virgilio

2013

Purinergic Signalling

272

265

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Receptors for extracellular nucleotides are widely expressed by mammalian cells. They mediate a large array of responses ranging from growth stimulation to apoptosis, from chemotaxis to cell differentiation and from nociception to cytokine release, as well as neurotransmission. Pharma industry is involved in the development and clinical testing of drugs selectively targeting the different P1 nucleoside and P2 nucleotide receptor subtypes. As described in detail in the present review, P2 receptors are expressed by all tumours, in some cases to a very high level. Activation or inhibition of selected P2 receptor subtypes brings about cancer cell death or growth inhibition. The field has been largely neglected by current research in oncology, yet the evidence presented in this review, most of which is based on in vitro studies, although with a limited amount from in vivo experiments and human studies, warrants further efforts to explore the therapeutic potential of purinoceptor targeting in cancer.

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“…Using activation of P2Y12 receptor as a biosensor for nucleotide release, it was suggested that spontaneous nucleotide release from PC12 cells occurs independently of vesicle exocytosis, whereas depolarization-evoked nucleotide release relies predominantly on exocytosis mechanisms (Hussl et al, 2007); however, the nature of released nucleotides was not determined in this study. Gardner et al, 2005 demonstrated using HPLC-FLD that ω-conotoxin GVIA had no effect on the KCl-evoked release of ATP in PC12 cells. In addition, they showed that endothelin-1 differentially modulated the release of ATP and dopamine, suggesting different sites or mechanisms of release of these substances in PC12 cells.…”

Section: Evidence For Release Of Purine Neurotransmittersmentioning

confidence: 96%

The purinergic neurotransmitter revisited: A single substance or multiple players?

Mutafova‐Yambolieva

Durnin

2014

Pharmacology & Therapeutics

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The past half century has witnessed tremendous advances in our understanding of extracellular purinergic signaling pathways. Purinergic neurotransmission, in particular, has emerged as a key contributor in the efficient control mechanisms in the nervous system. The identity of the purine neurotransmitter, however, remains controversial. Identifying it is difficult because purines are present in all cell types, have a large variety of cell sources, and are released via numerous pathways. Moreover, studies on purinergic neurotransmission have relied heavily on indirect measurements of integrated postjunctional responses that do not provide direct information for neurotransmitter identity. This paper discusses experimental support for adenosine 5′-triphosphate (ATP) as a neurotransmitter and recent evidence for possible contribution of other purines, in addition to or instead of ATP, in chemical neurotransmission in the peripheral, enteric and central nervous systems. Sites of release and action of purines in model systems such as vas deferens, blood vessels, urinary bladder and chromaffin cells are discussed. This is preceded by a brief discussion of studies demonstrating storage of purines in synaptic vesicles. We examine recent evidence for cell type targets (e.g., smooth muscle cells, interstitial cells, neurons and glia) for purine neurotransmitters in different systems. This is followed by brief discussion of mechanisms of terminating the action of purine neurotransmitters, including extracellular nucleotide hydrolysis and possible salvage and reuptake in the cell. The significance of direct neurotransmitter release measurements is highlighted. Possibilities for involvement of multiple purines (e.g., ATP, ADP, NAD+, ADP-ribose, adenosine, and diadenosine polyphosphates) in neurotransmission are considered throughout.

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Endothelin (ET)-1-Induced Inhibition of ATP Release from PC-12 Cells Is Mediated by the ET_BReceptor: Differential Response to ET-1 on ATP, Neuropeptide Y, and Dopamine Levels

Cited by 13 publications

References 37 publications

The Expression Level of Ecto-NTP Diphosphohydrolase1/CD39 Modulates Exocytotic and Ischemic Release of Neurotransmitters in a Cellular Model of Sympathetic Neurons

The Expression Level of Ecto-NTP Diphosphohydrolase1/CD39 Modulates Exocytotic and Ischemic Release of Neurotransmitters in a Cellular Model of Sympathetic Neurons

Purinergic signalling and cancer

The purinergic neurotransmitter revisited: A single substance or multiple players?

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Endothelin (ET)-1-Induced Inhibition of ATP Release from PC-12 Cells Is Mediated by the ETBReceptor: Differential Response to ET-1 on ATP, Neuropeptide Y, and Dopamine Levels

Cited by 13 publications

References 37 publications

The Expression Level of Ecto-NTP Diphosphohydrolase1/CD39 Modulates Exocytotic and Ischemic Release of Neurotransmitters in a Cellular Model of Sympathetic Neurons

The Expression Level of Ecto-NTP Diphosphohydrolase1/CD39 Modulates Exocytotic and Ischemic Release of Neurotransmitters in a Cellular Model of Sympathetic Neurons

Purinergic signalling and cancer

The purinergic neurotransmitter revisited: A single substance or multiple players?

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Product

Resources

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Endothelin (ET)-1-Induced Inhibition of ATP Release from PC-12 Cells Is Mediated by the ET_BReceptor: Differential Response to ET-1 on ATP, Neuropeptide Y, and Dopamine Levels