Signal transduction pathway for the substance P-induced inhibition of rat Kir3 (GIRK) channel.
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 approximately 10 s with intracellular GTPgammaS and approximately 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 Galpha(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 Galpha(q) to the channel.
Koike-Tani
Maki
M
Department of Anatomy and Cell Biology, 808 South Wood St, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
Collins
John M
JM
Kawano
Takeharu
T
Zhao
Peng
P
Zhao
Qi
Q
Kozasa
Tohru
T
Nakajima
Shigehiro
S
Nakajima
Yasuko
Y
D000818:Animals; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006801:Humans; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology / Q000502:physiology*
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D026941:Sodium Channel Blockers; D013373:Substance P
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