Kir3 (or GIRK) channels have been known for nearly three decades to be activated by direct interactions with
the βγ subunits of heterotrimeric G (Gαβγ) proteins in a membrane-delimited manner. Gα also interacts with GIRK channels
and since PTX-sensitive Gα subunits show higher affinity of interaction they confer signaling specificity to G Protein-
Coupled Receptors (GPCRs) that normally couple to these G protein subunits. In heterologous systems, overexpression
of non PTX-sensitive Gα subunits scavenges the available Gβγ and biases GIRK activation through GPCRs that couple
to these Gα subunits. Moreover, all Kir channels rely on their direct interactions with the phospholipid PIP2 to maintain
their activity. Thus, signals that activate phospholipase C (e.g. through Gq signaling) to hydrolyze PIP2 result in inhibition
of Kir channel activity. In this review, we illustrate with experiments performed in Xenopus oocytes that Kir channels
can be used efficiently as reporters of GPCR function through Gi, Gs or Gq signaling. The membrane-delimited nature
of this expression system makes it highly efficient for constructing dose-response curves yielding highly reproducible
apparent affinities of different ligands for each GPCR tested.
Keywords: GPCR, GIRK, G protein, PIP2, TEVC, Xenopus oocytes.
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