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J. Biol. Chem., Vol. 276, Issue 18, 14855-14860, May 4, 2001
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From the Department of Pharmacology University of Washington,
Seattle, Washington 98195-7280
We previously showed that activation of the human
endothelin A receptor (HETAR) by endothelin-1 (Et-1) selectively
inhibits the response to mu opioid receptor (MOR) activation of the
G-protein-gated inwardly rectifying potassium channel (Kir3). The Et-1
effect resulted from PLA2 production of an eicosanoid that inhibited Kir3. In this study, we show that Kir3 inhibition by eicosanoids is
channel subunit-specific, and we identify the site within the channel
required for arachidonic acid sensitivity. Activation of the
G-protein-coupled MOR by the selective opioid agonist
D-Ala2Glyol, enkephalin, released G
Eicosanoids Inhibit the G-protein-gated Inwardly Rectifying
Potassium Channel (Kir3) at the Na+/PIP2 Gating
Site*
that
activated Kir3. The response to MOR activation was significantly
inhibited by Et-1 activation of HETAR in homomeric channels composed of
either Kir3.2 or Kir3.4. In contrast, homomeric channels of Kir3.1 were
substantially less sensitive. Domain deletion and channel chimera
studies suggested that the sites within the channel required for
Et-1-induced inhibition were within the region responsible for channel
gating. Mutation of a single amino acid in the homomeric Kir3.1 to
produce Kir3.1(F137S)(N217D) dramatically increased the channel
sensitivity to arachidonic acid and Et-1 treatment. Complementary
mutation of the equivalent amino acid in Kir3.4 to produce
Kir3.4(S143T)(D223N) significantly reduced the sensitivity of the
channel to arachidonic acid- and Et-1-induced inhibition. The critical
aspartate residue required for eicosanoid sensitivity is the same
residue required for Na+ regulation of PIP2
gating. The results suggest a model of Kir3 gating that incorporates a
series of regulatory steps, including G, PIP2,
Na+, and arachidonic acid binding to the channel gating domain.
*
This study was supported by United States Public
Health Services Grant DA 04123 from the National Institute on Drug
Abuse.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Pharmacology, Box 357280, University of Washington, Seattle, WA
98195-7280. Tel.: 206-543-4266; Fax: 206-685-3822; E-mail:
cchavkin@u.washington.edu.
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