PIP2 is a necessary cofactor for ion channel function: how and why?

Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP2) is a minority phospholipid of the inner leaflet of plasma membranes. Many plasma membrane ion channels and ion transporters require PIP2 to function and can be turned off by signaling pathways that deplete PIP2. This review discusses the dependence of ion channels on phosphoinositides and considers possible mechanisms by which PIP2 and analogues regulate ion channel activity.

Figure 1

Crystal structure of the PH domain of DAPP1 (residues 162–261) bound to I(1,3,4,5)P₄. a, The protein component alone, with the main chain drawn as a ribbon and five basic residues drawn in stick form. Their contacting nitrogens are drawn as CPK balls. b, The full complex with I(1,3,4,5)P₄ represented in space-filling CPK form. The 1, 3, 4, and 5 phosphates are labeled. Colors: Blue nitrogen, red oxygen, orange phosphorus. Coordinates from (19).

Figure 2

Amino acid sequences of some putative phosphoinositide-binding domains. All basic residues are bold and red. Shown are the PH domains of DAPP1 and PLCδ1, the BED domain of MARCKS; the C-terminus of several GTPases, and the XIP domain of the Na⁺-Ca²⁺ exchanger (NCX1). Numbers below each sequence indicate the initial residue number.

Figure 3

Two extreme models for selective versus diffuse binding of poly-phosphoinositides. a, Specific PIP₂ interaction in a structured PIP₂ binding pocket structure and nonselective electrostatic PIP₂ attraction by polybasic peptides or polycations. b, A hypothesis suggesting a correlation between strong PIP₂ binding and high PIP₂ selectivity. The curve representing the number of channels in each category is completely hypothetical.

Figure 4

Ion channels and transporters sensitive to PIP₂. They include: Kir, inward rectifier K⁺ channel; Kv, voltage-gated K⁺ channel; HERG, human ether-à-go-go-related gene K⁺ channel; HCN channel, hyperpolarization-activated, CNG, cyclic nucleotide-regulated channel; Ca_v, voltage-gated Ca²⁺ channel; TRP, transient receptor potential; TrpL, TRP-like; CNG, cyclic nucleotide-gated channel; ENaC, epithelial Na⁺ channel; NCX, Na⁺-Ca²⁺ exchanger; NHE, Na⁺-H⁺ exchanger; NME, Na⁺-Mg²⁺ exchanger; PMCA, plasma membrane Ca²⁺ ATPase. Activation means increase of open probability, prevention of run down, or recovery from desensitization. Shift g-V means that the conductance-voltage relation is shifted along the voltage axis by PIP₂.

Figure 5

Putative PIP₂-interacting residues of ion channels. Shown are Kir2.1 (32, 45), β-ENaC (48, 94), KCNQ2 (95), and several TRP channels (5, 54, 69, 64). Basic amino acids experimentally implicated in PIP₂ binding are red, and other basic residues are shown in block bold. Hydrophobic residues implicated in PIP₂ binding are indicated by blue arrowheads (76, 96). The distal C-terminal sequence of TRPV1 implicated in inhibition by PIP₂ is green (64). Asterisks denote putative calmodulin binding sites. An open bar indicates a conserved PKKR domain in Kir channels involved in PIP₂ binding, and the closed bar indicates the highly conserved TRP box (XWK(F/X)QR). Numbers indicate the amino acid positions. M1–2 and S1–6 denote the transmembrane domains.