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Department of Molecular Biology of Neuronal Signals, Max-Planck
Institute for Experimental Medicine, Hermann-Rein-Str. 3, D-37075
Göttingen, Germany
We isolated a cDNA from human brain encoding a purinergic receptor that
shows a high degree of homology to the rat P2X4 receptor (87% identity). By fluorescence in situ hybridization,
the human P2X4 gene has been mapped to region q24.32 of
chromosome 12. Tissue distribution analysis of human P2X4
transcripts demonstrates a broad expression pattern in that the mRNA
was detected not only in brain but also in all tissues tested.
Heterologous expression of the human P2X4 receptor in
Xenopus laevis oocytes and human embryonic kidney 293 cells evoked an ATP-activated channel. Simultaneous whole-cell current
and Fura-2 fluorescence measurements in human embryonic kidney 293 cells transfected with human P2X4 cDNA allowed us to
determine the fraction of the current carried by Ca2+; this
was ~8%, demonstrating a high Ca2+ permeability. Low
extracellular Zn2+ concentrations (5-10 µM)
increase the apparent gating efficiency of human P2X4 by
ATP without affecting the maximal response. However, raising the
concentration of the divalent cation (>100 µM) inhibits the ATP-evoked current in a non-voltage-dependent manner. The human
P2X4 receptor displays a very similar agonist potency
profile to that of rat P2X4 (ATP 
2-methylthio-ATP 
CTP > 
,
-methylene-ATP > dATP) but has a notably higher sensitivity for the antagonists suramin,
pyridoxal-phosphate-6-azophenyl-2
,4-disulfonic acid, and bromphenol
blue. Chimeric constructs between human and rat isoforms as well as
single-point mutations were engineered to map the regions responsible
for the different sensitivity to suramin and
pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid.
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