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Signal transduction pathway for the substance P‐induced inhibition of rat Kir3 (GIRK) channel
Author(s) -
KoikeTani Maki,
Collins John M.,
Kawano Takeharu,
Zhao Peng,
Zhao Qi,
Kozasa Tohru,
Nakajima Shigehiro,
Nakajima Yasuko
Publication year - 2005
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2004.079285
Subject(s) - g protein coupled inwardly rectifying potassium channel , gtpgammas , immunoprecipitation , chemistry , g protein , intracellular , potassium channel , phosphatidylinositol , wild type , mutant , signal transduction , biology , biochemistry , biophysics , gene
Certain transmitters inhibit Kir3 (GIRK) channels, resulting in neuronal excitation. We analysed signalling mechanisms for substance P (SP)‐induced Kir3 inhibition in relation to the role of phosphatidylinositol 4,5‐bisphosphate (PIP 2 ). SP rapidly – with a half‐time of ∼10 s with intracellular GTPγS and ∼14 s with intracellular GTP – inhibits a robustly activated Kir3.1/Kir3.2 current. A mutant Kir3 channel, Kir3.1(M223L)/Kir3.2(I234L), which has a stronger binding to PIP 2 than does the wild type Kir3.1/Kir3.2, is inhibited by SP as rapidly as the wild type Kir3.1/Kir3.2. This result contradicts the idea that Kir3 inhibition originates from the depletion of PIP 2 . A Kir2.1 (IRK1) mutant, Kir2.1(R218Q), despite having a weaker binding to PIP 2 than wild type Kir3.1/Kir3.2, shows a SP‐induced inhibition slower than the wild type Kir3.1/Kir3.2 channel, again conflicting with the PIP 2 theory of channel inhibition. Co‐immunoprecipitation reveals that Gα q binds with Kir3.2, but not with Kir2.2 or Kir2.1. These functional results and co‐immunoprecipitation data suggest that G q activation rapidly inhibits Kir3 (but not Kir2), possibly by direct binding of Gα q to the channel.