Dr. Diomedes E. Logothetis
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Contact Information
Department of Physiology and Biophysics Virginia Commonwealth University P.O. Box 980551 Richmond, Virginia 23298-0551 Tel: 804-828-5878 Fax: 804-828-7382 email: delogothetis@vcu.edu |
Diomedes E. Logothetis received his undergraduate degree in Physics in 1980 and a Masters degree in Psychology in 1981 from Northeastern University in Boston. He received his Ph.D. in Physiology and Biophysics in 1987 from Harvard University under the mentorship of David Clapham. After completing postdoctoral training in the laboratories of Drs. Bernardo Nadal-Ginard and Peter Hess at Harvard Medical School, Dr. Logothetis joined the faculty at Mount Sinai School of Medicine in New York City at 1993. He joined the VCU faculty in 2008.
Research
My research program focuses on elucidating intracellular as well as cell-to-cell signaling mechanisms. My laboratory aims to understand the function of signaling systems making use of the information depicted in the three-dimensional structure of the macromolecules involved (proteins and lipids) and their interrelationships. We have focused on signaling mechanisms leading to the control of the activity of Ion Channel proteins. These transmembrane proteins underlie the proper rapid communication of our brain cells allowing processes such as thinking and memory to occur, the control of the rhythmic contraction of our hearts, the release of insulin from our pancreas, the proper transfer of solutes in our kidneys. When they malfunction they lead to devastating diseases, such as epilepsy, fatal cardiac arrhythmias, diabetes and hypertension. Understanding in molecular detail how their activity is regulated is essential if we aspire to develop therapeutic agents to control their function during disease.
Our research efforts have revealed a key element in the control of the activity of ion channels. The negatively charged lipid component of the plasma membrane phosphatidylinositol-bis-phosphate (PIP2) interacts with most ion channels and controls their activity. The negative charge of PIP2 comes from phosphate groups added onto its hydrophilic head. PIP2 levels in the plasma membrane are controlled by enzymes that remove all phosphates by cleaving the hydrophilic from the hydrophobic part (phospholipases) or by other enzymes that control progressive removal of phosphates (lipid phosphatases that eventually convert PIP2 to PI –phosphatidyl inositol) or by addition of phosphates (lipid kinases that progressively add 1, 2, or 3 phosphates to PI to make PIP, PIP2 or PIP3). PIP2 is the most abundant phosphoinositide in the plasma membrane and by virtue of electrostatic interactions with the channel protein it controls its gating (opening and closing). Our future work aims to understand in molecular terms how phosphoinositides control ion channel gating and how the action of many diverse modulators depends on the interactions of the channel with PIP2. Moreover, our recent work suggests that the control of the activity of membrane proteins by PIP2 is not limited to ion channel proteins but it extends to many other transmembrane protein types. We are quite interested in understanding how defects or alterations in the interactions of membrane proteins with PIP2 can lead to disease.
A second area of focus centers around GTP binding (G) protein signaling, particularly through the bg subunits of G proteins (Gbg). Signaling through G protein coupled receptors is ubiquitous throughout every cell in our bodies and many pharmaceutical companies devote a major part of their efforts in developing drugs to control signaling through these receptors. Ion channels, present a unique assay with which to learn about the physiology of G protein signaling. The lab is interested in questions addressing the molecular mechanisms of specificity of Gbg signaling, the molecular details of how the macromolecular complex (receptor/G proteins/effector) works together to signal efficiently and the crosstalk of signals conveyed to the cell by different G protein signaling pathways.
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 ion channels. Expression of recombinant channels in Xenopus oocytes and mammalian cell lines, cell isolation methods and tissue culture techniques are used routinely towards mechanistic studies. Computational approaches, such as molecular dynamics simulations of protein structures generate experimentally testable models. Fluorescence microscopy is used to localize the channel proteins in cells and tissues and to explore their interactions with other macromolecules.
Teaching
I have always enjoyed teaching. At both of my previous two institutions, Harvard Medical School and Mount Sinai School of Medicine, I lectured on Membrane Excitability / Ion Channels and Cardiovascular Physiology and directed laboratory exercises in Medical Physiology. At Mount Sinai I directed the Medical Physiology course for two years and also a Core Cell Biology course for five years. In addition, I organized and directed a graduate level course on “Ion Channels” for over 10 years and a “Methods in Biomedical Sciences” course for two years. I also participated in several other courses in Neurobiology, Pharmacology, Physiology, Biophysics and Cell Biology. At Virginia Commonwealth University I am participating in the graduate level “Cardiovascular Physiology - PHIS 612” course (Spring 2008) and I have also been invited to participate during the Fall 2008 in the “Cellular and Molecular Neuroscience - ANAT/PHIS/PHTX 509” course and in the “M1 Medical Physiology” course.
Selected Publications
Original Work:
Logothetis DE, Kurachi Y, Galper J, Neer EJ, Clapham DE. The beta gamma subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. Nature. 1987 Jan 22-28;325(6102):321-6.
Pub Med
Kobrinsky E, Mirshahi T, Zhang H, Jin T, Logothetis DE. Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nat Cell Biol. 2000 Aug;2(8):507-14.
Pub Med
Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE. Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies.
Neuron. 2002 Jun 13;34(6):933-44.
Pub Med
Zhang H, Craciun LC, Mirshahi T, Rohács T, Lopes CM, Jin T, Logothetis DE. PIP2 activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron. 2003 Mar 27;37(6):963-75.
Pub Med
Rohács T, Lopes CM, Michailidis I, Logothetis DE. PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nat Neurosci. 2005 May;8(5):626-34. Epub 2005 Apr 24.
Pub Med
Michailidis IE, Helton TD, Petrou VI, Mirshahi T, Ehlers MD, Logothetis DE. Phosphatidylinositol-4,5-bisphosphate regulates NMDA receptor activity through alpha-actinin. J Neurosci. 2007 May 16;27(20):5523-32.
Pub Med
Reviews:
Logothetis DE, Jin T, Lupyan D, Rosenhouse-Dantsker A. Phosphoinositide-mediated gating of inwardly rectifying K+ channels. Pflugers Arch. 2007 Oct;455(1):83-95. Epub 2007 May 23.
Pub Med
Logothetis DE, Lupyan D, Rosenhouse-Dantsker A. Diverse Kir modulators act in close proximity to residues implicated in phosphoinositide binding. J Physiol. 2007 Aug 1;582(Pt 3):953-65. Epub 2007 May 10. Review.
Pub Med