Phosphoinositide-mediated gating of inwardly rectifying K+ channels

Abstract

Phosphoinositides, such as phosphatidylinositol-bisphosphate (PIP(2)), control the activity of many ion channels in yet undefined ways. Inwardly, rectifying potassium (Kir) channels were the first shown to be dependent on direct interactions with phosphoinositides. Alterations in channel-PIP(2) interactions affect Kir single-channel gating behavior. Aberrations in channel-PIP(2) interactions can lead to human disease. As the activity of all Kir channels depends on their interactions with phosphoinositides, future research will aim to understand the molecular events that occur from phosphoinositide binding to channel gating. The determination of atomic resolution structures for several mammalian and bacterial Kir channels provides great promise towards this goal. We have mapped onto the three-dimensional channel structure the position of basic residues identified through mutagenesis studies that contribute to the sensitivity of a Kir channel to PIP(2). The localization of these putative PIP(2)-interacting residues relative to the channel's permeation pathway has given rise to a testable model, which could account for channel activation by PIP(2).

Mutations in Nature Conferred a High Affinity Phosphatidylinositol 4,5-Bisphosphate-binding Site in Vertebrate Inwardly Rectifying Potassium Channels

“…Prokaryotic Kir channels are inhibited by PIP 2 (11,12), whereas Kir channels from all eukaryotic cells studied to date are activated by PIP 2 (2,6,10,13). This is an interesting difference, but PIP 2 is not present in the prokaryotic cell membrane (2,6), and thus its inhibitory effect on bacterial Kir channels lacks physiological relevance. Among eukaryotes, the structural basis for Kir channel activation by PIP 2 has been clarified by many studies (1,2), culminating in the co-crystallization of PIP 2 with chicken Kir2.2 (7).…”

Stoichiometry of Kir channels with phosphatidylinositol bisphosphate

“…9,10 Kir channels are the ion channel family, whose dependence on phosphoinositides, and in particular on phosphatidylinositol bisphosphate (PIP 2 ) that is the most abundant plasma membrane phosphoinositide, has been studied most comprehensively (reviewed in refs. [11][12][13][14][15][16][17][18][19]. Despite intense studies of Kir channel interactions with phosphoinositides, the number of PIP 2 molecules controlling channel activity is not known.…”

Identification of Novel Cholesterol-binding Regions in Kir2 Channels

“…This region has also been implicated in the control of Kir2 gating, and it was proposed that interactions between the N and C termini provide a tangential force that mechanically gates the channel (62). Moreover, it has been recently suggested (63) that rearrangements in the interactions pattern between the N and C termini of Kir channels occur when the channels are activated by phosphatidylinositol 4,5-bisphosphate, a major regulator of channel function, which is required for activation of Kir channels (37,62,64,65). We propose, therefore, that interactions between cholesterol and residues located in region 2 may affect the gating mechanism that leads to the opening of the inner helix gate while bending the pore-lining helix at the central glycine hinge.…”