Phosphoinositides (PIs) are rare phospholipids in cell membranes. The simplest form, phosphatidylinositol, is the most abundant of the family. It can be phosphorylated by specific cytoplasmic lipid kinases and dephosphorylated by lipid phosphatases on the 3, 4, and 5 positions of the inositol ring, giving a combinatorial panel of seven phosphorylated forms. The resulting phosphoinositides acquire interesting signaling roles by interaction with proteins rather than having structural roles in the architecture of the lipid bilayer. Each phosphorylated PI is the signature lipid of one of the cellular organelles that attracts specific collections of soluble cytoplasmic proteins to the organelle through protein-lipid interactions specific for the headgroup. These proteins are considered peripheral proteins characteristic of the organelle. The complement of peripheral proteins on a membrane changes abruptly during membrane traffic as the phosphoinositides of the membrane are reworked. Phosphatidylinositol 4,5-bisphosphate is the signature lipid of the plasma membrane. This phosphoinositide is loosely called PIP2, and more carefully, PI(4,5)P2. With Byung-Chang Suh, we found that PI(4,5)P2 is also an essential cofactor for the ion channel, KCNQ, and an enhancer of some voltage-gated calcium channels. The importance of such interactions becomes apparent as a decrease of current when plasma membrane PI(4,5)P2 is depleted by activating phospholipase C coupled receptors. This mode of ion channel modulation is common in the nervous system. We developed many tools to up- and-down regulate PI(4,5)P2 and other membrane phosphoinositides and proved that the KCNQ channel protein of the plasma membrane has an absolute requirement for PI(4,5)P2. Many plasma membrane ion channels are thought to be similarly dependent on PI(4,5)P2. Such findings elevate the importance of learning more about the metabolism, interconversion, and display of cellular phosphoinositides. We are trying to use cell biological tools and biophysical methods to follow their synthesis, trafficking, and significance throughout the cell.
Research Activities :
Honors and Awards :
- 1986: Elected Member of the USA National Academy of Sciences
- 1990: 3rd Annual Bristol-Myers Squibb Award for Distinguished Achievement in Neuroscience Research, shared with Erwin Neher (Germany) and Jean-Pierre Changeux (France)
- 1996: Columbia University Annual Louisa Gross Horwitz Prize for Outstanding Basic Research in Biology or Biochemistry, shared with Clay Armstrong
- 1999: Albert Lasker Award for Basic Medical Research, shared with Clay Armstrong and Roderick MacKinnon 2001 Gairdner Fdn. International Award, for outstanding discoveries or contributions to Medical Science, shared with Clay Armstrong and Roderick MacKinnon
- 2002: Elected Member of the National Academies’ Institute of Medicine