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  • Title: Gating of G protein-sensitive inwardly rectifying K+ channels through phosphatidylinositol 4,5-bisphosphate.
    Author: Logothetis DE, Zhang H.
    Journal: J Physiol; 1999 Nov 01; 520 Pt 3(Pt 3):630. PubMed ID: 10545130.
    Abstract:
    Several inwardly rectifying K+ channels show an ATP-dependent rundown of their activity. Hydrolysis of ATP is required for maintenance of channel activity. G protein-gated inwardly rectifying K+ (GIRK) channels also depend on ATP hydrolysis for gating by sodium ions or the [beta][gamma] subunits of G proteins (Sui et al. 1998). Strong evidence suggests that phosphatidylinositol 4, 5-bisphosphate (PIP2), synthesized via the hydrolysis of ATP, is absolutely required for channel gating (Sui et al. 1998; Huang et al. 1998). Interestingly, Huang and colleagues (Huang et al. 1998) showed that G[beta][gamma] subunits (the [beta][gamma] subunits of GTP-binding proteins) caused a stabilization of channel-PIP2 interactions, suggesting that G[beta][gamma] subunits may gate the channel through PIP2. Ho & Murrell-Lagnado (1999b) recently identified an aspartate residue responsible for gating these K+ channels. Ho & Murrell-Lagnado (1999a) in this issue of The Journal of Physiology present evidence that sodium ions also stabilize channel-PIP2 interactions. They suggest that Na+ effectively neutralizes a negatively charged residue, somehow promoting interactions of the channel with PIP2. These results on the mechanism of Na+ action are in close agreement with recently published work from our group. Zhang et al. (1999) showed that two C-terminal cytoplasmic arginine residues, which interact with PIP2, are localized next to the identified aspartate residue that is responsible for the Na+ effects on gating. Thus, the implication from the results of these three studies (Huang et al. 1998; Zhang et al. 1999; Ho & Murrell-Lagnado, 1999a) is that stabilization of channel-PIP2 interactions may be a common mechanism for gating GIRK channels by molecules as different as Na+ or the G[beta][gamma] subunits (see Fig. 1). These results raise many interesting questions on how modulation of channel-PIP2 interactions may lead to channel gating. Are the channel-PIP2 sites that are stabilized by G[beta][gamma] subunits shared with those that are affected by Na+? Na+ seems to act by screening the electrostatic effects that the aspartate residue exerts on the nearby PIP2-interacting arginines. How does G[beta][gamma] binding lead to stabilization of channel- PIP2 interactions? Is the Na+ sensitivity of the channel used physiologically and if so how does it relate to signalling through G proteins? Structural data for these channels and in particular for their cytoplasmic portions, which are critical for interactions with PIP2, will greatly aid our molecular understanding of the conformations needed for channel gating. Finally, although the dependence of GIRK channel activity on PIP2 is clear, it is not known yet whether the levels of PIP2 needed for channel gating are constant or under regulatory control. Answers to these and many other such questions are likely to shed light on the mechanism by which PIP2 itself serves as an important regulator of the activity of membrane proteins.
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