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Vol. 54, Issue 1, 22-32, July 1998
Department of Physiology and Biophysics, School of Medicine, Case
Western Reserve University, Cleveland, Ohio 44106 (B.D.H., J.R.,
G.R.D.), and
Glaxo Institute for Molecular Biology, Plan-les-Ouates,
1228 Geneva, Switzerland (C.V., A.S.)
1-[N,O-Bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine
(KN-62) and
N-[1-[N-methyl-p-(5
isoquinolinesulfonyl)benzyl]-2-(4 phenylpiperazine)ethyl]-5-isoquinolinesulfonamide (KN-04) potently inhibit the human lymphocyte P2Z receptor, an ATP-gated cation channel
[Br J Pharmacol 120:1483-1490 (1997)].
Although the molecular identity of the lymphocyte P2Z receptor has not been established, it shares many functional characteristics with the
cloned P2X7 nucleotide receptor. We have tested whether
these isoquinolines inhibit P2X receptor function in human embryonic kidney 293 cells that stably express the human or rat recombinant P2X7 receptors. ATP activation of cation currents and
uptake of the organic dye ethidium were potently inhibited by KN-62 and KN-04 in human embryonic kidney cells expressing the human
P2X7R but not the rat P2X7R, even though these
species homologues share 80% amino acid identity. Introduction of the
first 335 amino acids of the human P2X7R sequence conferred
KN-62 sensitivity to the rat P2X7R; this suggests that
isoquinolines interact with residues in the amino-terminal half
(containing the large extracellular loop) of the human
P2X7R. KN-62 and KN-04 also potently inhibited ATP-gated
Ca2+ influx and ethidium uptake in several leukocyte cell
lines (THP-1, BAC1.2f5, and BW5147) that natively express the human or
murine P2X7R mRNA. The ability of isoquinoline sulfonamides
to potently inhibit human and murine P2X7R signaling will
be a useful tool for identifying P2Z/P2X7 functional
responses in other cell types. The substantial differences in
pharmacological sensitivity between rat and human P2X7R may
also indicate structural domains important in channel/pore activation.
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