G protein-gated inwardly rectifying K+ (GIRK) channels were the first example of an effector that is directly regulated by the beta-gamma subunits of G proteins. However, relatively little is known about the elements on the Gbeta-gamma that are important for GIRK channel regulation. We have previously used a chimeric strategy to identify important elements on the channel that are important for regulation by Gbeta-gamma (He et. al. 1999). Here, we present preliminary data indicating that in Xenopus oocytes, Gbeta1-beta4 can all activate the GIRK channels with similar efficacy. However, the Gbeta5 is incapable of activating these channels under identical conditions. Western blot analysis in oocytes expressing Gbeta5 showed that the protein is expressed. Therefore lack of expression can not be responsible for lack of channel activation. Sequence alignment showed that Gbeta1-beta4 display approximately 90% identity, whereas Gbeta5 shows only 51 % identity with other Gbeta subunits. Based on these findings, we propose to use a chimeric strategy between Gbeta1 and Gbeta5 to identify the regions responsible for the difference in channel activation by the two subunits. Once these regions are identified, we will use mutagenesis to identify specific residues involved in the interaction of Gbeta1 and the channel. These studies will help us better understand the interaction of G proteins with GIRK channels. The proposed studies will also help us achieve a better understanding of G protein mediate signaling, which is of major physiological importance.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-HEM-2 (01))
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Mount Sinai School of Medicine
Schools of Medicine
New York
United States
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Mirshahi, Tooraj; Logothetis, Diomedes E (2004) Molecular determinants responsible for differential cellular distribution of G protein-gated inwardly rectifying K+ channels. J Biol Chem 279:11890-7
Zhang, Hailin; Craciun, Liviu C; Mirshahi, Tooraj et al. (2003) PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37:963-75
Peng, Luying; Mirshahi, Tooraj; Zhang, Hailin et al. (2003) Critical determinants of the G protein gamma subunits in the Gbetagamma stimulation of G protein-activated inwardly rectifying potassium (GIRK) channel activity. J Biol Chem 278:50203-11
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Jin, Taihao; Peng, Luying; Mirshahi, Tooraj et al. (2002) The (beta)gamma subunits of G proteins gate a K(+) channel by pivoted bending of a transmembrane segment. Mol Cell 10:469-81
Mirshahi, Tooraj; Robillard, Liliane; Zhang, Hailin et al. (2002) Gbeta residues that do not interact with Galpha underlie agonist-independent activity of K+ channels. J Biol Chem 277:7348-55