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As SK-N-MC cells express different P2X subunits, the Javier Gualix et al.
possible formation of heteromeric assemblies, in which
P2X4 subunits were present, should be taken into formation of oligomers, a process commonly referred to as
consideration. Three different P2X4-containing receptor dimerization. There is evidence that P2Y1
heteromeric channels have been described so far: P2X1/4, receptors can form both homodimers and heteromeric
P2X4/6 and P2X4/7 receptors (48-50). P2X4/7 complexes with the P2Y11 or A1 receptors (61, 62). Such
heteromeric receptor shares some of the pharmacological kinds of interaction will contribute to add complexity to
properties of the P2X receptor in the SK-N-MC cells, as it the purinergic signalling
is potentiated by ivermectin (48). However there is a clear
difference between both receptors: heteromeric P2X4/7 5. CONCLUSIONS
receptor is activated by BzATP (48) whereas the P2X
receptor in SK-N-MC cells has been proved to be In summary, P2Y1 and P2X4 receptors are widespread
insensitive to this nucleotide analog. Regarding P2X1/4 in the CNS where they can participate in a number of
and P2X4/6 receptors, the phenotype of such heteromers different and important functions. As these receptors are
differs in some aspects from that of P2X4. For example, constitutively expressed and functional in SK-N-MC cells,
heteromeric P2X1/4 and P2X4/6 receptors are activated by such cells can constitute a useful model with which
low concentrations of a,ß-meATP, whereas homomeric analyze several aspects of the physiology of both
P2X4 receptors are relatively insensitive to this substance nucleotide receptors. These include their regulation,
(49, 50). As P2X receptors in SK-N-MC cells appear to be associated intracellular signalling pathways,
unaffected by a,ß-me-ATP, it seems more probable that oligomerization, cross-talk with other neurotransmitter
they were formed by a homomeric combination of P2X4 systems and putative implication in neurological or
subunits rather than a heteromeric combination of P2X4 neurodegenerative disorders.
with the P2X1 or the P2X6 subunits. However, as SK-N-
MC cells also express some additional P2X subunit, such 6. ACKNOWLEDGMENTS
as P2X5, a heteromeric association between this subunit
and the P2X4 one can not be ruled out. This work was supported by research grants from
Ministerio de Ciencia e Innovación (BFU2014-53654-P)
Taken together, these pharmacological data likely and Comunidad de Madrid (S2013/ICE-2958 BRADE-
indicate the presence of two functional P2 receptors in the CM).
human neuroblastoma SK-M-MC cell line: one
metabotropic, P2Y1, and the other ionotropic, P2X4 (or a 7. ABBREVIATIONS LIST
heteromeric channel including the P2X4 subunit).
Responses to ADP and its derivatives will be mediated 2-MeSADP, 2-methylthyo-adenosine-5'-diphosphate;
trough the activation of the P2Y1 receptor, although a,ß-meATP, a,ß-methylene-adenosine 5'-triphosphate;
responses to ATP will be due to the interaction of such ADPßS, adenosine-5'-0-(2-thiodiphosphate); APP,
nucleotide with both the P2Y1 and the P2X4 receptors. amyloid precursor protein; BSA, bovine serum albumin;
CTP, on their hand, will only activate the ionotropic P2X4 BzATP, 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-
receptor. triphosphate; ERK1/2, extracellular signal-regulated
protein kinase 1/2; Fura-2 AM, fura-2 acetoxymethyl ester;
P2X4 receptor, which is expressed in several regions of MAPKs, mitogen-activated protein kinases; MRS2179,
the brain and spinal cord (51, 52), has received N6-methyl-2'-deoxyadenosine-3',5'-bisphosphate; PBS,
considerable recent attention due to its emerging role in phosphate-buffered saline; PKC, protein kinase C;
the modulation of chronic inflammatory and neurophatic PPADS, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic
pain (53-55). There are also evidences suggesting that acid; TNP-ATP, 2',3'-O-(2,4,6-trinitrophenyl)adenosine 5'-
P2X4 receptors could be involved in the mechanism triphosphate.
sustaining neuronal cell death caused by oxygen/glucose
deprivation (56, 57). More recently, a role of the P2X4 8. REFERENCES
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