The NUIN Student Sponsored Seminar Series presents
26 Apr 2010 – 12:00 pm to 01:15 pm
LOCATION: Baldwin Auditorium, Lurie Medical Research Building, 303 E. Superior St., Chicago Campus
G PROTEIN COUPLED RECEPTORS REGULATE ION CHANNELS AND MANY OTHER MEMBRANE PROTEINS THROUGH PHOSPHOINOSITIDE BREAKDOWN
Membrane proteins are immersed in a bilayer sea of lipid. Among membrane lipids, the rare polyphosphoinositide phospholipids serve a signaling role rather than a membrane structural role. They are ZIP codes identifying the membrane of each organelle. Many proteins including some ion channels require them to function. For the plasma membrane, phosphatidylinositol 4,5-bisphosphate (PIP2) is the zip code. When receptors such as M1 muscarinic receptors that couple to the G protein Gq are stimulated, phospholipase C is activated, plasma membrane PIP2 is cleaved, and many potent downstream second messengers are generated. However, these well-studied messengers are not the only signals produced. We found that some PIP2-requiring membrane proteins are turned off by M1 receptor activation because the PIP2 becomes depleted in a few seconds (1). Indeed such regulation probably applies to many membrane proteins. Our work recognized the PIP2-depletion signal through studies on GPCR modulation of ion channels, specifically of suppression of ion current in KCNQ K+ channels and in several voltage-gated Ca2+ channels. We exploited tools to measure and manipulate membrane phosphoinositides within seconds (2), and we measured the kinetics of the events in the full cascade from receptor to PIP2 turnover and resynthesis (3). All of these events have been successfully incorporated into a kinetic model for this signaling system (4, 5). A rapid turnover of specific phosphoinositides probably occurs on each of the intracellular membranes as well and regulates a wide range of organellar activities.
Supported by grants from the NIH: NS08174 and GM83913.
1. Suh BC, Hille B. Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron. 2002; 35:507-20.
2. Suh BC, Inoue T, Meyer T, Hille B. Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science. 2006; 314:1454-7.
3. Jensen JB, Lyssand JS, Hague C, Hille B. Fluorescence changes reveal kinetic steps of muscarinic receptor-mediated modulation of phosphoinositides and Kv7.2/7.3 K+ channels. J Gen Physiol. 2009; 133:347-59.
4. Falkenburger, B.H., J.B. Jensen, and B. Hille. 2010. Kinetics of M1 muscarinic receptor and G-protein signaling to phospholipase C in living cells. J. Gen. Physiol. 135: 81-97. PMCID: PMC2812500
5. Falkenburger, B.H., J.B. Jensen, and B. Hille. 2010. Kinetics of PIP2 metabolism and KCNQ2/3 channel regulation studied with a voltage-sensitive phosphatase in living cells. J. Gen. Physiol. 135: 99-114, 2010. PMCID: PMC2812502