The complex and intriguing lives of PIP2 with ion channels and transporters.

Phosphatidylinositol-4,5-bisphosphate (PIP(2)), the precursor of several signaling molecules in eukayotic cells, is itself also used by cells to signal to membrane-associated proteins. PIP(2) anchors numerous signaling molecules and cytoskeleton at the cell membrane, and the metabolism of PIP(2) is closely connected to membrane trafficking. Recently, ion transporters and channels have been discovered to be regulated by PIP(2). Systems reported to be activated by PIP(2) include (i) plasmalemmal calcium pumps (PMCA), (ii) cardiac sodium-calcium exchangers (NCX1), (iii) sodium-proton exchangers (NHE1-4), (iv) a sodium-magnesium exchanger of unknown identity, (v) all inward rectifier potassium channels (KATP, IRK, GIRK, and ROMK channels), (vi) epithelial sodium channels (ENaC), and (vii) ryanodine-sensitive calcium release channels (RyR). Systems reported to be inhibited by PIP(2) include (i) cyclic nucleotide-gated channels of the rod (CNG), (ii) transient receptor potential-like (TRPL) Drosophila phototransduction channels, (iii) capsaicin-activated transient receptor potential (TRP) channels (VR1), and (iv) IP(3)-gated calcium release channels (IP3R). Systems that appear to be completely insensitive to PIP(2) include (i) voltage-gated sodium channels, (ii) most voltage-gated potassium channels, (iii) sodium-potassium pumps, (iv) several neurotransmitter transporters, and (v) cystic fibrosis transmembrane receptor (CFTR)-type chloride channels. Presumably, local changes of the concentration of PIP(2) in the plasma membrane represent cell signals to those mechanisms sensitive to PIP(2) changes. Unfortunately, our understanding of how local PIP(2) concentrations are regulated remains very limited. One important complexity is the probable existence of phospholipid microdomains, or lipid rafts. Such domains may serve to localize PIP(2) and thereby PIP(2) signaling, as well as to organize PIP(2) binding partners into signaling complexes. A related biological role of PIP(2) may be to control the activity of ion transporters and channels during biosynthesis or vesicle trafficking. Low PIP(2) concentrations in the secretory pathway would inactivate all of the systems that are stimulated by PIP(2). How, in detail, is PIP(2) used by cells to control ion channel and transporter activities? Further progress requires an improved understanding of lipid kinases and phosphatases, how they are regulated, where they are localized in cells, and with which ion channels and transporters they might localize.