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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
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentMicrobiology and Physiological Systems

    InstitutionUMMS - School of Medicine
    DepartmentNeuroNexus Institute

    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


    Collapse Biography 
    Collapse education and training
    Mount Holyoke College, South Hadley, MA, United StatesABBiology
    Boston University, Boston, MA, United StatesPHDBiology

    Collapse Overview 
    Collapse overview

    Calcium Channels and Neuronal Plasticity


    Profile in the process of being updated (4/12/17)


    My laboratory is interested in understanding the role that voltage-gated Ca2+ channel (VGCC) subunits play in the body. In neurons, influx of Ca2+ through these channels serves the critical function of interfacing electrical signals with biochemical and transcriptional changes. Variability in their level of expression, cell-surface location and activity has profound effects on how much and where Ca2+ enters a nerve cell. This in turn influences neurotransmitter release, the strength of synaptic contacts as well as cellular and transcriptional processes, which ultimately affect learning and behavior. At the cellular level, my lab has focused on understanding how neuro­trans­mitters, small lipid molecules, and cytoplasmic proteins modulate postsynaptic neuronal VGCC activity and VGCC activity in pancreatic b-cells. These basic questions about VGCC function overlap with our interest in understanding the cellular basis of schizophrenia. Explore the lab webpage to learn more about the lab’s research interests. 


    Four potential levels of plasticity for neuronal calcium channels are being examined in this lab: Using whole cell and single channel patch clamp recording techniques we are asking1) what are the underlying causes of the different endogenous patterns of activity observed in single channel currents and 2)how does channel behavior change when it is modulated by neurotransmitters and other cellular signals? Using molecular techniques, including Northern blot analysis and RNase protection assays we are trying to determine 3) what regulates the level of expression of the four protein subunits that make up different calcium channels and 4) do calcium channels switch subunits?


    Research Figure


     



    Collapse 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.


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    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Liu L, Bonventre JV, Rittenhouse AR. cPLA2a-/- sympathetic neurons exhibit increased membrane excitability and loss of N-Type Ca2+ current inhibition by M1 muscarinic receptor signaling. PLoS One. 2018; 13(12):e0201322. PMID: 30557348.
      View in: PubMed
    2. Roberts-Crowley ML, Rittenhouse AR. Modulation of CaV1.3b L-type calcium channels by M1 muscarinic receptors varies with CaVß subunit expression. BMC Res Notes. 2018 Sep 27; 11(1):681. PMID: 30261922.
      View in: PubMed
    3. Ortiz-Miranda S, Ji R, Jurczyk A, Aryee KE, Mo S, Fletcher T, Shaffer SA, Greiner DL, Bortell R, Gregg RG, Cheng A, Hennings LJ, Rittenhouse AR. A novel transgenic mouse model of lysosomal storage disorder. Am J Physiol Gastrointest Liver Physiol. 2016 Nov 01; 311(5):G903-G919. PMID: 27659423.
      View in: PubMed
    4. Jurczyk A, Nowosielska A, Przewozniak N, Aryee KE, DiIorio P, Blodgett D, Yang C, Campbell-Thompson M, Atkinson M, Shultz L, Rittenhouse A, Harlan D, Greiner D, Bortell R. Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic ß-cell function via glycogen synthase kinase-3ß. FASEB J. 2016 Feb; 30(2):983-93. PMID: 26546129.
      View in: PubMed
    5. Roberts-Crowley ML, Rittenhouse AR. Characterization of ST14A Cells for Studying Modulation of Voltage-Gated Calcium Channels. PLoS One. 2015; 10(7):e0132469. PMID: 26147123.
      View in: PubMed
    6. Huang F, Bladon J, Lagoy RC, Shorrock PN, Hronik-Tupaj M, Zoto CA, Connors RE, McGimpsey WG, Molnar P, Lambert S, Rittenhouse AR, Lambert CR. A photosensitive surface capable of inducing electrophysiological changes in NG108-15 neurons. Acta Biomater. 2015 Jan; 12:42-50. PMID: 25449922.
      View in: PubMed
    7. 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. PMID: 24861006.
      View in: PubMed
    8. Rittenhouse AR. Novel coupling is painless. J Gen Physiol. 2014 Apr; 143(4):443-7. PMID: 24688017.
      View in: PubMed
    9. 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. PMID: 22846993.
      View in: PubMed
    10. 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. PMID: 19858358.
      View in: PubMed
    11. 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. PMID: 19858357.
      View in: PubMed
    12. 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. PMID: 19419761.
      View in: PubMed
    13. 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. PMID: 19332620.
      View in: PubMed
    14. 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. PMID: 18247369.
      View in: PubMed
    15. Rittenhouse AR. PIP2 PIP2 hooray for maxi K+. J Gen Physiol. 2008 Jul; 132(1):5-8. PMID: 18562503.
      View in: PubMed
    16. 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. PMID: 17673503.
      View in: PubMed
    17. 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. PMID: 17331208.
      View in: PubMed
    18. 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. PMID: 17093080.
      View in: PubMed
    19. 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. PMID: 15004729.
      View in: PubMed
    20. 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. PMID: 12842134.
      View in: PubMed
    21. Liu L, Rittenhouse AR. Pharmacological discrimination between muscarinic receptor signal transduction cascades with bethanechol chloride. Br J Pharmacol. 2003 Apr; 138(7):1259-70. PMID: 12711626.
      View in: PubMed
    22. 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. PMID: 12496347.
      View in: PubMed
    23. 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. PMID: 11287344.
      View in: PubMed
    24. 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. PMID: 11287343.
      View in: PubMed
    25. 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. PMID: 10835042.
      View in: PubMed
    26. Barrett CF, Rittenhouse AR. Modulation of N-type calcium channel activity by G-proteins and protein kinase C. J Gen Physiol. 2000 Mar; 115(3):277-86. PMID: 10694257.
      View in: PubMed
    27. N'Gouemo P, Rittenhouse AR. Biophysical and pharmacological characterization of voltage-sensitive calcium currents in neonatal rat inferior colliculus neurons. Neuroscience. 2000; 96(4):753-65. PMID: 10727793.
      View in: PubMed
    28. Rittenhouse AR, Zigmond RE. Role of N- and L-type calcium channels in depolarization-induced activation of tyrosine hydroxylase and release of norepinephrine by sympathetic cell bodies and nerve terminals. J Neurobiol. 1999 Aug; 40(2):137-48. PMID: 10413445.
      View in: PubMed
    29. Rittenhouse AR, Parker C, Brugnara C, Morgan KG, Alper SL. Inhibition of maxi-K currents in ferret portal vein smooth muscle cells by the antifungal clotrimazole. Am J Physiol. 1997 Jul; 273(1 Pt 1):C45-56. PMID: 9252441.
      View in: PubMed
    30. Rittenhouse AR, Vandorpe DH, Brugnara C, Alper SL. The antifungal imidazole clotrimazole and its major in vivo metabolite are potent blockers of the calcium-activated potassium channel in murine erythroleukemia cells. J Membr Biol. 1997 May 15; 157(2):177-91. PMID: 9151659.
      View in: PubMed
    31. Rittenhouse AR, Hess P. Microscopic heterogeneity in unitary N-type calcium currents in rat sympathetic neurons. J Physiol. 1994 Jan 1; 474(1):87-99. PMID: 8014899.
      View in: PubMed
    32. Rittenhouse AR, Zigmond RE. Omega-conotoxin inhibits the acute activation of tyrosine hydroxylase and the stimulation of norepinephrine release by potassium depolarization of sympathetic nerve endings. J Neurochem. 1991 Feb; 56(2):615-22. PMID: 1671089.
      View in: PubMed
    33. Rittenhouse AR, Schwarzschild MA, Zigmond RE. Both synaptic and antidromic stimulation of neurons in the rat superior cervical ganglion acutely increase tyrosine hydroxylase activity. Neuroscience. 1988 Apr; 25(1):207-15. PMID: 2899305.
      View in: PubMed
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