Many potassium channels require phosphatidyl inositol 4,5bisphosphate (PIP2), a major membrane phospholipid, for their activity. We have successfully shown that PIP2 hydrolysis in response to receptor stimulation inhibits channel activity. Factors that affect PIP2 metabolism or the interaction between the channel and PIP2 modulate channel activity and this may represent a major mechanism for regulating the activity of these channels. Several of these channels are subject to modulation by alcohol and volatile anesthetics and we are testing whether these effects are mediated through alteration in the channel-PIP2 interaction.
Potassium channel structure and function is highly preserved across species indicating their critical role in cellular physiology. We have recently isolated an ATP sensitive potassium channel from zebrafish and shown that it shares many characteristics with its mammalian counterparts. Given the unique utility of zebrafish as a model organism, we are pursuing ways to explore the physiology of these channels in vivo.
Figure 1. How do Kir channels open? Upper panel shows a closed Kir3.4 channel in the membrane. The pore is depicted in white, the selectivity filter is shown in green, and the narrowest part of the pore is shown in orange. The transmembrane and cytoplasmic domains of the channel are shown in white; the Gβγ interacting region in cyan, and specific residues that interact with Gβγ in dark blue. Residues that interact with PIP2 are shown in purple. Gβ is drawn in pink, Gγ is drawn in gray, and Gα is drawn in yellow. A (-) marker in red circles depicts PIP2 molecules in the membrane. The lower panel shows an open Kir3.4 channel. Gβγ that has dissociated from Gα interacts with the cytoplasmic domains in Kir3.4, leading to enhanced interaction of the Kir3.4 cytoplasmic regions with PIP2 in the membrane. This interaction exerts a pulling force on the pore, leading to the widening of the gate marked in orange. (Adapted from Mirshahi et al Science STKE 2003)
