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    Ann R Rittenhouse PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-3735
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell and Molecular Physiology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative

        Academic Background

        A.B., Mount Holyoke College, 1976
        Ph.D., Boston University, 1984.

        Calcium Channels and Neuronal Plasticity

        Photo: Ann R. RittenhouseMy laboratory is interested in understanding the role that voltage-activated calcium channels play in neural plasticity. While plasticity of the brain at the level of complex human behavior is quite obvious,it is also apparent at the cellular level.

        One initial site for plasticity occurs with the influx of calciumthrough voltage-activated calcium channels. Calcium influx servesa unique function of acting as a bridge between electrical andbiochemical signaling in nerve cells. Variability in calcium channelkinetics and level and site of expression has profound effectson how much and where calcium enters a nerve cell. This in turninfluences the strength of the synaptic contacts a nerve cellmakes and on the underlying cellular and molecular processes thatoccur. Four potential levels of plasticity for neuronal calciumchannels are being examined in this lab: Using whole cell andsingle channel patch clamp recording techniques we are asking1) what are the underlying causes of the different endogenouspatterns of activity observed in single channel currents and 2)how does channel behavior change when it is modulated by neurotransmittersand other cellular signals? Using molecular techniques, includingNorthern blot analysis and RNase protection assays we are tryingto determine 3) what regulates the level of expression of thefour protein subunits that make up different calcium channelsand 4) do calcium channels switch subunits?

        Research Figure

        Rotation Projects

        Rotation Projects

        p>My lab has been interested in N-type calcium (Ca) channels because of their special position in the nervous system. They coordinate electrical activity occurring at the cell membrane with underlying biochemical and transcriptional events. N-type Ca channels are found only in nerve cells and neuronally-derived tissues, are associated with the regulation of transmitter synthesis, and release from most presynaptic nerve endings. They are the most extensively modulated Ca channels in the brain in that more pathways exist for their modulation than for any other type. Because of their role in transmission and high degree of modulation, they may be a critical player in certain types of synaptic plasticity. Indeed, much of what is termed neural plasticity ultimately starts at synapses and involves Ca influx. N-type Ca channels display endogenous, heterogeneous activity, called modes, defined as patterns of activity that are stable for much longer periods of time (sec to min) than are transitions between channel closings and openings. Because transitions among modes result in qualitative changes in channel activity, these channels can be considered plastic.

        Students will use both whole cell and single channel patch clamp and molecular techniques to test aspects of our model that attempts to explain N-type Ca channel plasticity. The following assumptions can be tested using recombinant channels in HEK cells, or native channels in sympathetic, cortical and/or striatal neurons. 1) Modes are the result of reversible modification of the channel, e.g., phosphorylation/dephosphorylation, G-protein binding/dissociation, etc. 2) Signaling cascades that converge at a critical site on the channel, such as a phosphorylation site, are predicted to affect the same mode. 3) Modification of the channel at one site is independent of modifications occurring at other sites. 4) Modification of the channel at multiple sites may occur simultaneously, giving rise to these complex patterns of activity. 5) Complex activity can be deconstructed into simpler, reversible reactions.

        Schematic of N-type Ca channel modulation in sympathetic neurons
        Figure 1. Schematic of N-type Ca channel modulation in sympathetic neurons. The transmitters listed exert their actions on Ca channels by activating signal transduction cascades that stimulate/liberate one or more of the following signaling molecules: AA, PKC and the G-protein subunits Gao and Gbg. Multi-transmitter effects may converge on these channels in cell bodies during presynaptic release of acetylcholine and peptides or in endings due to feedback from released norepinephrine and peptides.

        The implication of this model is that these layers of variability, observed at the level of the N-type Ca channel activity, may be building blocks that underlie emergent forms of plasticity, observed at the level of synapses and neural circuits. Moreover, some of the signaling cascades, which converge to modulate N-type Ca channel activity, are pathways that appear disrupted in certain disorders such as Alzheimer's Disease, schizophrenia and stroke. Thus, understanding these basic principles of channel modulation may reveal insights into these disorders.

        Selected Lab References

        Liwang Liu and Ann R. Rittenhouse (2000) Effects of Arachidonic Acid on Unitary Calcium Currents in Rat Sympathetic Neurons. J. Physiology, 525: 391- 404.

        Curtis F. Barrett and Ann R. Rittenhouse (2000) Modulation of N-type Calcium Channel Activity by G-Proteins and Protein Kinase C. J. General Physiology, 115: 1-11. See Commentary: B.P. Bean (2000) Modulating Modulation. J. General Physiology, 115: 273 - 275.

        Liwang Liu, Curtis F. Barrett and Ann R. Rittenhouse (2001) Arachidonic Acid both Enhances and Inhibits Calcium Currents in Sympathetic Neurons. Am. J. Physiology, 280: C1293 - C1305.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. diIorio P, Rittenhouse AR, Bortell R, Jurczyk A. Role of cilia in normal pancreas function and in diseased states. Birth Defects Res C Embryo Today. 2014 Jun; 102(2):126-38.
          View in: PubMed
        2. Rittenhouse AR. Novel coupling is painless. J Gen Physiol. 2014 Apr; 143(4):443-7.
          View in: PubMed
        3. Gabriel L, Lvov A, Orthodoxou D, Rittenhouse AR, Kobertz WR, Melikian HE. The acid-sensitive, anesthetic-activated potassium leak channel, KCNK3, is regulated by 14-3-3ß-dependent, protein kinase C (PKC)-mediated endocytic trafficking. J Biol Chem. 2012 Sep 21; 287(39):32354-66.
          View in: PubMed
        4. 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
        5. Mitra-Ganguli T, Vitko I, Perez-Reyes E, Rittenhouse AR. Orientation of palmitoylated CaVbeta2a relative to CaV2.2 is critical for slow pathway modulation of N-type Ca2+ current by tachykinin receptor activation. J Gen Physiol. 2009 Nov; 134(5):385-96.
          View in: PubMed
        6. 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
        7. Roberts-Crowley ML, Rittenhouse AR. Arachidonic acid inhibition of L-type calcium (CaV1.3b) channels varies with accessory CaVbeta subunits. J Gen Physiol. 2009 Apr; 133(4):387-403.
          View in: PubMed
        8. Liu L, Heneghan JF, Michael GJ, Stanish LF, Egertová 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
        9. Rittenhouse AR. PIP2 PIP2 hooray for maxi K+. J Gen Physiol. 2008 Jul; 132(1):5-8.
          View in: PubMed
        10. 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
        11. 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
        12. 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
        13. 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
        14. 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
        15. 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
        16. 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
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