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1 Department of Pharmacology
2 Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL, 60612, USA
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 (PIP2). SP rapidly – with a half-time of 
10 s with intracellular GTP
S 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 PIP2 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 PIP2. A Kir2.1 (IRK1) mutant, Kir2.1(R218Q), despite having a weaker binding to PIP2 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 PIP2 theory of channel inhibition. Co-immunoprecipitation reveals that G
q binds with Kir3.2, but not with Kir2.2 or Kir2.1. These functional results and co-immunoprecipitation data suggest that Gq activation rapidly inhibits Kir3 (but not Kir2), possibly by direct binding of Gq to the channel.
(Received 15 November 2004;
accepted after revision 22 February 2005;
first published online 24 February 2005)
Corresponding author Y. Nakajima: Department of Anatomy and Cell Biology, 808 South Wood St, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. Email: yasukon{at}uic.edu
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