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    Liwang Liu MD

    TitleResearch Assistant Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentPsychiatry
    AddressUniversity of Massachusetts Medical School
    303 Belmont Street
    Worcester MA 01605
    Phone508-856-8160
        Overview 
        Narrative

        Molecular and Cellular Basis of Ion Channels in Physiology and Pathophysiology

        Photo Liwang Liu, MD

        Ion channels are crucial components for the activity of living cells. They are integral proteins in the cell membrane and allow particular ions to pass through them. The transmembrane movement of ions through specific channels is a fundamental mechanism in the regulation of cell function in all tissues. Modifications of the activities of these ion channels well evoke changes in the membrane potential that are associated with the inhibition, modulation or termination of cellular activities. The changes of ion channel activities play very important roles in many physiological and pathophysiological processes. My long-term research goal is to understand the molecular and cellular basis of ion channels, regulation of ion channels, and their roles in inherited and environmentally-induced diseases and to provide useful information towards developing new preventive and therapeutic methods in the management and/or rectification of pathophysiological conditions.

        My major research works focus on voltage-gated calcium (Ca2+) channels. Voltage-gated Ca2+channels found in all excitable cells and many non-excitable cells mediate Ca2+ ion influx in response to membrane depolarization. Ca2+ entering into cell through voltage-gated Ca2+ channels regulates several biological processes including gene transcription, muscle contraction, hormone secretion, and neurotransmitter release. Ca2+ channels are classified into several groups (L-, N-, P/Q-, R- and T-types) based on their electrophysiological, molecular biological and pharmacological properties. They are composed of four principal subunits: the transmembrane, pore-forming alsubunits and three accessory subunits that modulate channel function--the glycosylated a2d subunits, the integral membraneg subunits, and the cytoplasmic ß subunits. There are several isoforms of each of these channel subunits, and the composition of the channel complex determines its expression level, localization, kinetics, and pharmacology. The activity of Ca2+ channels is regulated by a wide variety of intracellular signaling pathways. Probably the three most well understood are binding and activation of calmodulin, phosphorylation by several protein kinases, and binding of G protein bgsubunits. These pathways not only modulate Ca2+ channel activity, all are themselves modulated in various ways by Ca2+ influx through Ca2+ channels, and many interact with one another. Thus, complex feedback mechanisms among Ca2+ channels and intracellular signaling exist and are likely targets for both environmental toxicants and genetic disorders. There are two fundamentally different mechanisms that might alter Ca2+ channel function: by direct interaction with channel subunits (e.g., block the pore) or by interaction with intracellular signaling pathways that modulate channel activity. A large number of neurotransmitters or toxicants are known to alter intracellular signaling pathways and/or alter Ca2+ homeostasis, but how these effects impact Ca2+ channel function remains largely unexplored. Therefore, to understand cellular and molecular mechanisms of modulation of Ca2+ channel activities will be increase our understanding of their roles in physiology and pathophysiology, as well as potential target for therapeutics.



        Bibliographic 
        selected publications
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        1. Liu L, Zhao-Shea R, McIntosh JM, Gardner P, Tapper A. Nicotine Persistently Activates Ventral Tegmental Area Dopaminergic Neurons Via Nicotinic Acetylcholine Receptors Containing a4 and a6 subunits. Mol Pharmacol. 2012 Jan 5.
          View in: PubMed
        2. Zhao-Shea R, Liu L, Soll LG, Improgo MR, Meyers EE, McIntosh JM, Grady SR, Marks MJ, Gardner PD, Tapper AR. Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. Neuropsychopharmacology. 2011 Apr; 36(5):1021-32.
          View in: PubMed
        3. Heneghan JF, Mitra-Ganguli T, Stanish LF, Liu L, Zhao R, Rittenhouse AR. The Ca2+ channel beta subunit determines whether stimulation of Gq-coupled receptors enhances or inhibits N current. J Gen Physiol. 2009 Nov; 134(5):369-84.
          View in: PubMed
        4. Roberts-Crowley ML, Mitra-Ganguli T, Liu L, Rittenhouse AR. Regulation of voltage-gated Ca2+ channels by lipids. Cell Calcium. 2009 Jun; 45(6):589-601.
          View in: PubMed
        5. Liu L, Heneghan JF, Michael GJ, Stanish LF, Egertov√° M, Rittenhouse AR. L- and N-current but not M-current inhibition by M1 muscarinic receptors requires DAG lipase activity. J Cell Physiol. 2008 Jul; 216(1):91-100.
          View in: PubMed
        6. Liu L, Heneghan JF, Mitra-Ganguli T, Roberts-Crowley ML, Rittenhouse AR. Role of PIP2 in regulating versus modulating Ca2+ channel activity. J Physiol. 2007 Sep 15; 583(Pt 3):1165-6; author reply 1167.
          View in: PubMed
        7. Zhao R, Liu L, Rittenhouse AR. Ca2+ influx through both L- and N-type Ca2+ channels increases c-fos expression by electrical stimulation of sympathetic neurons. Eur J Neurosci. 2007 Feb; 25(4):1127-35.
          View in: PubMed
        8. Liu L, Zhao R, Bai Y, Stanish LF, Evans JE, Sanderson MJ, Bonventre JV, Rittenhouse AR. M1 muscarinic receptors inhibit L-type Ca2+ current and M-current by divergent signal transduction cascades. J Neurosci. 2006 Nov 8; 26(45):11588-98.
          View in: PubMed
        9. Liu L, Roberts ML, Rittenhouse AR. Phospholipid metabolism is required for M1 muscarinic inhibition of N-type calcium current in sympathetic neurons. Eur Biophys J. 2004 May; 33(3):255-64.
          View in: PubMed
        10. Liu L, Gonzalez PK, Barrett CF, Rittenhouse AR. The calcium channel ligand FPL 64176 enhances L-type but inhibits N-type neuronal calcium currents. Neuropharmacology. 2003 Aug; 45(2):281-92.
          View in: PubMed
        11. Liu L, Rittenhouse AR. Pharmacological discrimination between muscarinic receptor signal transduction cascades with bethanechol chloride. Br J Pharmacol. 2003 Apr; 138(7):1259-70.
          View in: PubMed
        12. Liu L, Rittenhouse AR. Arachidonic acid mediates muscarinic inhibition and enhancement of N-type Ca2+ current in sympathetic neurons. Proc Natl Acad Sci U S A. 2003 Jan 7; 100(1):295-300.
          View in: PubMed
        13. Barrett CF, Liu L, Rittenhouse AR. Arachidonic acid reversibly enhances N-type calcium current at an extracellular site. Am J Physiol Cell Physiol. 2001 May; 280(5):C1306-18.
          View in: PubMed
        14. Liu L, Barrett CF, Rittenhouse AR. Arachidonic acid both inhibits and enhances whole cell calcium currents in rat sympathetic neurons. Am J Physiol Cell Physiol. 2001 May; 280(5):C1293-305.
          View in: PubMed
        15. Liu L, Rittenhouse AR. Effects of arachidonic acid on unitary calcium currents in rat sympathetic neurons. J Physiol. 2000 Jun 1; 525 Pt 2:391-404.
          View in: PubMed
        16. Liu LW, Costa G, Schallenberg G, Trinco R. Shiftwork and heat stress in an intensive care unit. J Tongji Med Univ. 1994; 14(2):98-104.
          View in: PubMed
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