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Cited by 115Adenosine and Purinergic SignalingIon Channels and ReceptorsCalcium signaling and nucleotide metabolism

Effects of antagonists at the human recombinant P2X7 receptor

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Chessell, I. P., Michel, A. D., Humphrey, P. P. A.·1998·British Journal of Pharmacology
DOI 10.1038/sj.bjp.0701958PMC PMC1565513
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Abstract

We have used whole‐cell patch clamping methods to examine the properties of the recombinant human P2X 7 (P2Z) receptor stably expressed in HEK‐293 cells. In an extracellular solution with lowered concentrations of divalent cations (zero Mg 2+ and 0.5 m m Ca 2+), both ATP and the nucleotide analogue, 2′‐ and 3′‐O‐(4‐benzoylbenzoyl)‐adenosine 5′‐triphosphate (Bz‐ATP) evoked concentration‐dependent whole‐cell inward currents with maxima of 4658±671 and 5385±990 pA, respectively, at a holding potential of −90 mV. Current‐voltage relationships determined using 100 μ m Bz‐ATP reversed at −2.7±3.1 mV, and did not display significant rectification. Repeated applications of 300 μ m Bz‐ATP produced inward currents with similar rise‐times (approx. 450 ms, 5–95% current development) but with progressively slower 95–5% decay times, with the eighth application of this agonist yielding a decay time of 197% of the first application. Concentration‐effect curves to ATP and Bz‐ATP produced estimated EC 50 values of 780 and 52.4 μ m, respectively. Consecutive concentration‐effect curves to Bz‐ATP produced curves with similar maxima and EC 50 values. The non‐selective P2 antagonists, pyridoxal‐phosphate‐6‐azophenyl‐, 2′,4′‐disulphonic acid (PPADS) and suramin, both produced concentration‐dependent increases in maximal inward currents to Bz‐ATP, with IC 50 concentrations of approximately 1 μ m and 70 μ m, respectively. The profile of antagonism produced by PPADS was not that of a competitive antagonist. The isoquinolene derivatives 1‐(N,O‐bis[5‐isoquinolinesulphonyl]‐N‐methyl‐l‐tyrosyl)‐4‐phenylpiperazine (KN‐62) and calmidazolium both produced antagonism which was not competitive, with IC 50 concentrations of approximately 15 and 100 n m, respectively. HMA (5‐(N,N‐hexamethylene)‐ amiloride) was also an effective antagonist at a concentration of 10 μ m. The group IIb metal, copper, also displayed antagonist properties at the human P2X 7 receptor, reducing the maximum response to Bz‐ATP by about 50% at a concentration of 1 μ m. These data demonstrate that the human recombinant P2X 7 receptor displays functional behaviour which is similar to the recombinant rat P2X 7 receptor, but has a distinct pharmacological profile with respect to agonist and antagonist sensitivity. British Journal of Pharmacology (1998) 124, 1314–1320; doi:10.1038/sj.bjp.0701958

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  • The P2X7 receptor is a trimeric ionotropic receptor with low affinity for ATP (EC50 around 0.3-1.8 mM) and, under prolonged stimulation, can form pores allowing the passage of large hydrophilic molecules.

    “The P2X7 receptor is a trimeric ionotropic receptor that belongs to the P2X family of purinergic receptors, presenting low affinity for ATP (EC50 around 0.3–1.8 mM) and, under prolonged stimulation, can form pores allowing the passage of large hydrophilic molecules [62–64].”

    From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [63]

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Authors
Chessell, I. P., Michel, A. D., & Humphrey, P. P. A.
Affiliations
University of Cambridge (GB)
Corresponding author
Chessell, I. P.
Venue
British Journal of Pharmacology
Publisher
Wiley
Published
1998-07
Volume
124
Issue
6
Pages
1314-1320
ISSN
  • 0007-1188 (ISSN-L)
  • 1476-5381
DOI
10.1038/sj.bjp.0701958
PMC
PMC1565513
OpenAlex
W2049146381
Cited by
115
References
22
Citations by year
2026: 1 · 2025: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 5
FWCI
5.31
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3878 d)
Locations
  • British Journal of Pharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
P2X7 receptor, purinergic receptor antagonists, PPADS, suramin, KN-62, calmidazolium, HMA, amiloride, divalent cation dependence, non-competitive antagonism, receptor desensitization, HEK293 cells
MeSH terms
Adenosine Triphosphate, Cell Line, Humans, Recombinant Proteins, Receptors, Purinergic P2X7, Purinergic P2 Receptor Antagonists

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