Phosphoinositide regulation of inward rectifier potassium (Kir) channels

Abstract

Inward rectifier potassium (Kir) channels are integral membrane proteins charged with a key role in establishing the resting membrane potential of excitable cells through selective control of the permeation of K+ ions across cell membranes. In conjunction with secondary anionic phospholipids, members of this family are directly regulated by phosphoinositides (PIPs) in the absence of other proteins or downstream signaling pathways. Different Kir isoforms display distinct specificities for the activating PIPs but all eukaryotic Kir channels are activated by PI(4,5)P2. On the other hand, the bacterial KirBac1.1 channel is inhibited by PIPs. Recent crystal structures of eukaryotic Kir channels in apo and lipid bound forms reveal one specific binding site per subunit, formed at the interface of N- and C-terminal domains, just beyond the transmembrane segments and clearly involving some of the key residues previously identified as controlling PI(4,5)P2 sensitivity. Computational, biochemical, and biophysical approaches have attempted to address the energetic determinants of PIP binding and selectivity among Kir channel isoforms, as well as the conformational changes that trigger channel gating. Here we review our current understanding of the molecular determinants of PIP regulation of Kir channel activity, including in context with other lipid modulators, and provide further discussion on the key questions that remain to be answered.

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).…”

“…3C. To negate the impact of the initial (on-cell) current value on the strength of the re-activation by PIP 2 in each construct, we compared the magnitude of the recovered current after AASt PIP 2 (Fig. 4D, black bars) with the on-cell current amplitude before rundown (Fig.…”

“…PIP 2 is a known regulator of many ion channel and transport molecules (1,2). The solution of two crystal structures of vertebrate Kir channels complexed with PIP 2 highlights the interaction of positively charged residues between the transmembrane domain and the C terminus with the negatively charged headgroup phosphates (7,45).…”

“…Multiple positively charged residues located in the N and C termini of vertebrate Kir channels are important in coordinating with the negatively charged headgroup phosphates of PIP 2 (1,2,7,45). Do the various basic residues play equivalent roles?…”

“…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). Among the critical components of the protein-lipid interaction are several basic residues within the channel that provide an electrostatically favorable interaction with the negative charges on the phosphate groups of PIP 2 .…”