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Member Information
J. Kevin Foskett, PhD
Professor, Department of Physiology
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Keywords: physiology, cell biology
Research and/or Clinical Interests:
Interaction of HIV nef with intracellular calcium release ion channels.
Summary:
Human (HIV) and simian (SIV) immunodeficiency viruses contain genes that encode for accessory proteins that exert important influences in target cells in vivo which are critical for infectivity and disease progression. The nef gene codes for a protein that is synthesized early in the viral life cycle and is expressed at high levels. Nef is required for maintaining high viral loads and for development of pathogenic AIDS. Its importance is underscored by the finding that a significant cohort of HIV-infected humans that experience long-term survival or non-progression of HIV-1 infection have the nef gene modified or deleted. A major role for Nef in disease progression is believed to be by its influence on T-cell activation, a process that is associated with an increase in intracellular Ca 2+ concentration, which is derived initially from release from intracellular stores, and which regulates the expression of important genes. We have discovered that Nef interacts with the intracellular Ca 2+ release channel, the InsP 3 receptor (InsP 3 R), and that this interaction causes a profound inhibition of the gating (opening and closing) of the channel. Our goal is to determine the physiological relevance of these observations by extending these preliminary studies to determine whether Nef and the InsP 3 R interact directly; to determine which isoforms of the channel interact with Nef, and conversely, which Nef isolates interact with the channel; and to determine the mechanisms of Nef inhibition of channel activi ty. We anticipate that these studies will provide novel insights into the cellular physiology of HIV infection.
Representative Publications:
Mak, D-O.D, S. McBride, V. Raghuram, Y. Yue, S.K.Joseph and J.K. Foskett. 2000. Single channel properties in endoplasmic reticulum membrane of recombinant type 3 inositol trisphosphate receptor. J. Gen. Physiol. . 115:241-255.
Mak, D.O.D, S. McBride and J.K. Foskett. 2001. ATP-dependent adenophostin activation of InsP 3 receptor channel gating. Kinetic implications for the durations of calcium puffs in cells. J. Gen. Physiol. 117:299-314.
Boehning , D., D.-O.D. Mak, J.K. Foskett and S.K. Joseph. 2001. Molecular determinants of permeation and selectivity in inositol 1,4,5-trisphosphate receptor Ca 2+ channels. J. Biol. Chem. 276:13509-13512.
Mak, D.O.D, S. McBride and J.K. Foskett. 2001. Regulation by Ca 2+ and inositol 1,4,5-trisphosphate (InsP 3 ) of single recombinant type 3 InsP 3 receptor channels. Ca 2+ activation uniquely distinguishes types 1 and 3 InsP 3 receptors. J. Gen. Physiol. 117:435-446.
Mak, D.O.D, S. McBride and J.K. Foskett. 2001. ATP regulation of recombinant type 3 inositol 1,4,5-trisphosphate receptor gating. J. Gen. Physiol . 117:447-456.
Boehning, D., S.K. Joseph, D.-O.D. Mak and J.K. Foskett. 2001. Single-channel recordings of recombinant inositol trisphosphate receptors in mammalian nuclear envelope. Biophysical J. 81:117-124.
Yang, J., S. McBride, D.-O. D. Mak, F. Haeseleer, K. Palczewski and J. K. Foskett. 2002. Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca 2+ release channels. Proc. Nat. Acad. Sci . 99:7711-7716.
Zeng, W., D.O.D. Mak , Q. Li, D. M. Shin, J. K. Foskett and S. Muallem. 2003. A new mode of Ca 2+ signaling by G protein-coupled receptors: Gating of IP 3 receptor Ca 2+ release channels by G???? Current Biol . 13:872-876.
