- ADJUNCT PROFESSOR Structural and Chemical Biology
Harvard Medical School
Ph.D., Harvard University
Vice Chairman, Department of Physiology and Biophysics
Laboratory Web Site: http://inka.mssm.edu/~diomedes (Research, Members, Events)
ResearchOur laboratory studies G protein-mediated signal transduction mechanisms that regulate cell excitability. Our studies provided the first example of the effector function of the beta-gamma subunits of GTP-binding proteins. We are interested in understanding the mechanism of G protein-mediated activation of a class of Potassium channels, which in response to external signals are responsible for such functions as the slowing down of heart rate and the inhibition of neurotransmitter release. Using molecular techniques we aim to identify specific G protein-channel interactions and the mechanism by which they affect channel function. \r\n\r\n
In parallel studies, we have recently discovered that the large family of potassium channel proteins, that include the G protein-sensitive channels, function by direct interactions with phosphatidylinositol phospholipids in the plasma membrane. G protein signaling is likely to activate these channels conformationally by adjusting channel phospholipid interactions. Moreover, signaling pathways that regulate the level of these phospholipids critically affect the function of these potassium channels. \r\n\r\n\r\n
Cardiac and neuronal cells of the central nervous system, where these channels are prevalent, are isolated from heart and brain and are studied electrophysiologically. Transgenic models with defects in G proteins or the potassium channel are used to elucidate the functional importance of these molecules in the particular tissue and the whole organism. \r\n\r\n\r\n
The lab employs electrophysiological techniques to assay ion channel function (patch clamp, two-electrode voltage clamp). Molecular biological techniques are used to clone and perform structure-function studies on these potassium channels. Expression of recombinant channels in Xenopus oocytes and mammalian cell lines are used routinely towards mechanistic studies. Cell isolation methods and tissue culture techniques are also routinely used. Confocal microscopy is used to localize the channel proteins in cells and tissues. \r\n\r\n
Sui JL, Petit-Jacques J, Logothetis D. Activation of the atrial KACh channel by the betagamma subunits of G proteins or intracellular Na+ ions depends on the presence of phosphatidylinositol phosphates. Proc Natl Acad Sci U S A 1998 Feb 3; 95(3): 1307-12.
Rohacs T, Chen J, Prestwich GD, Logothetis D. Distinct specificities of inwardly rectifying K(+) channels for phosphoinositides. J Biol Chem 1999 Dec 17; 274(51): 36065-72.
Petit-Jacques J, Su JL, Logothetis D. Synergistic activation of G protein-gated inwardly rectifying potassium channels by the betagamma subunits of G proteins and Na(+) and Mg(2+) ions. J Gen Physiol 1999 Nov; 114(5): 673-84.
Pabon A, Chan K, Sui JL, Wu X, Logothetis D, Thornhill WB. Glycosylation of GIRK1 at asn119 and ROMK1 at asn117 has different consequences in potassium channel function. J Biol Chem 2000 Sep 29; 275(39): 30677-82.
Kobrinsky E, Mirshahi T, Zhang H, Jin T, Logothetis D. Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nat Cell Biol 2000 Aug; 2(8): 507-14.
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