Targeted Deletion of Ectonucleoside Triphosphate Diphosphohydrolase 1/CD39 Leads to Desensitization of Pre- and Postsynaptic Purinergic P2 Receptors

Schäefer, Ulrich; Machida, Takuji; Broekman, M. Johan; Marcus, Aaron J.; Levi, Roberto

doi:10.1124/jpet.107.125328

Cited by 22 publications

(14 citation statements)

References 42 publications

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“…Entpd1 null mice exhibit decreased synaptic efficacy, presumably due to desensitization P2X1 receptors (34,35). However in the cochlea, Entpd1 gene deletion had little effect, if any, on hearing, but this lack of effect may result from the coexpression of other ectonucleotidases -NTPDase2 and NTPDase8 -normally present in that epithelium (36).…”

Section: Discussionmentioning

confidence: 90%

Role of the ectonucleotidase NTPDase2 in taste bud function

Vandenbeuch

Anderson²,

Parnes³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Taste buds are unusual in requiring ATP as a transmitter to activate sensory nerve fibers. In response to taste stimuli, taste cells release ATP, activating purinergic receptors containing the P2X2 and P2X3 subunits on taste nerves. In turn, the released ATP is hydrolyzed to ADP by a plasma membrane nucleoside triphosphate previously identified as nucleoside triphosphate diphosphohydrolase-2 (NTPDase2). In this paper we investigate the role of this ectonucleotidase in the function of taste buds by examining gene-targeted Entpd2-null mice globally lacking NTPDase2. RT-PCR confirmed the absence of NTPDase2, and ATPase enzyme histochemistry reveals no reaction product in taste buds of knockout mice, suggesting that NTPDase2 is the dominant form in taste buds. RT-PCR and immunocytochemistry demonstrated that in knockout mice all cell types are present in taste buds, even those cells normally expressing NTPDase2. In addition, the overall number and size of taste buds are normal in Entpd2-null mice. Luciferin/luciferase assays of circumvallate tissue of knockout mice detected elevated levels of extracellular ATP. Electrophysiological recordings from two taste nerves, the chorda tympani and glossopharyngeal, revealed depressed responses to all taste stimuli in Entpd2-null mice. Responses were more depressed in the glossopharyngeal nerve than in the chorda tympani nerve and involved all taste qualities; responses in the chorda tympani were more depressed to sweet and umami stimuli than to other qualities. We suggest that the excessive levels of extracellular ATP in the Entpd2-knockout animals desensitize the P2X receptors associated with nerve fibers, thereby depressing taste responses.purinergic signaling | synaptic function | E-NTPDase | mouse | gustatory T aste buds, the sensory end organs of gustation, are unique among the special senses in using ATP as a key transmitter to activate their sensory nerve fibers (1). The gustatory nerves express the purinergic receptor subunits P2X2 and P2X3 (2), which rapidly depolarize the nerve terminal when exposed to ATP. An important feature of neurotransmission is the removal of transmitter from extracellular space to prevent desensitization of the receptors by prolonged exposure to the ligand. In the case of taste buds, removal of ATP is accomplished largely by one of the eight known ectonucleotidases (for a review, see ref.3), nucleoside triphosphate diphosphohydrolase-2 (NTPDase2), a highly specific nucleoside triphosphate diphosphohydrolase (4, 5), which preferentially degrades ATP over ADP (6), (i.e., an ectoATPase, as defined histochemically by specificity for ATP).The NTPDase of taste buds is expressed by only one of the three principal types of cells within the bud. Each taste bud contains an onion-shaped cluster of 50-100 elongate taste cells, comprising morphologically and molecularly distinct cell types (for review, see ref. 7): type I, type II, and type III. The detection and transduction of different tastants is accomplished by type II and type III cells (for review...

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Section: Discussionmentioning

confidence: 90%

Role of the ectonucleotidase NTPDase2 in taste bud function

Vandenbeuch

Anderson²,

Parnes³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…It does not seem too far-fetched to propose that the enzymes are strategically distributed so as to influence the activity of P2 and P1 purinoceptors through the generation, or hydrolysis, of agonists such as ATP, ADP or adenosine. In addition, it is possible that ectonucleotidases prevent desensitisation of tubular P2 receptors, as has been demonstrated in other tissues [76][77][78]. Finally, it has been hypothesised that in conditions such as ischaemia, the ectonucleotidase-mediated modulation of the inhibitory effects of nucleotides on water and electrolyte reabsorption might be overwhelmed by excess ATP release, thereby reducing energy-consuming reabsorptive processes [79].…”

Section: Discussionmentioning

confidence: 97%

Ectonucleotidases in the kidney

Shirley

Vekaria

Sévigny

2009

Purinergic Signalling

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Members of all four families of ectonucleotidases, namely ectonucleoside triphosphate diphosphohydrolases (NTPDases), ectonucleotide pyrophosphatase/ phosphodiesterases (NPPs), ecto-5′-nucleotidase and alkaline phosphatases, have been identified in the renal vasculature and/or tubular structures. In rats and mice, NTPDase1, which hydrolyses ATP through to AMP, is prominent throughout most of the renal vasculature and is also present in the thin ascending limb of Henle and medullary collecting duct. NTPDase2 and NTPDase3, which both prefer ATP over ADP as a substrate, are found in most nephron segments beyond the proximal tubule. NPPs catalyse not only the hydrolysis of ATP and ADP, but also of diadenosine polyphosphates. NPP1 has been identified in proximal and distal tubules of the mouse, while NPP3 is expressed in the rat glomerulus and pars recta, but not in more distal segments. Ecto-5′-nucleotidase, which catalyses the conversion of AMP to adenosine, is found in apical membranes of rat proximal convoluted tubule and intercalated cells of the distal nephron, as well as in the peritubular space. Finally, an alkaline phosphatase, which can theoretically catalyse the entire hydrolysis chain from nucleoside triphosphate to nucleoside, has been identified in apical membranes of rat proximal tubules; however, this enzyme exhibits relatively high K m values for adenine nucleotides. Although information on renal ectonucleotidases is still incomplete, the enzymes' varied distribution in the vasculature and along the nephron suggests that they can profoundly influence purinoceptor activity through the hydrolysis, and generation, of agonists of the various purinoceptor subtypes. This review provides an update on renal ectonucleotidases and speculates on the functional significance of these enzymes in terms of glomerular and tubular physiology and pathophysiology.

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“…Because ATP availability greatly increases in myocardial ischemia, it has been suggested that recombinant E-NTPDase 1/CD39 may offer a novel therapeutic approach to the damage caused by ischemia by reducing sympathetic activity (Corti et al, 2011). E-NTPDase 1/CD39 deletion led to an attenuation of the activity of sympathetic pre-and postsynaptic P2X receptors (attributed to P2X receptor desensitization) perhaps because of prolonged exposure to ATP that accompanies E-NTPDase 1/CD39 deletion, and it was suggested that E-NTPDase 1/CD39 can potentially prevent the transition from myocardial ischemia to infarction (Schaefer et al, 2007).…”

Section: Ischemiamentioning

confidence: 99%