Photo of Elizabeth A. Eipper, Ph.D.

Elizabeth A. Eipper, Ph.D.

Professor, Department of Molecular Biology and Biophysics
Academic Office Location:
Molecular Biology and Biophysics
UConn Health
263 Farmington Avenue
Farmington, CT 06030-3401
Phone: 860-679-8898
Fax: 860-679-1885
Website(s): Molecular Biology & Biochemistry Graduate Program
Neuroscience Graduate Program
Neuropeptide Lab Page
Education
DegreeInstitutionMajor
Ph.D.Harvard UniversityBiophysics
M.S.Brown UniversityPhysical Chemistry
B.S.Brown UniversityPhysical Chemistry

Post-Graduate Training
TrainingInstitutionSpecialty
FellowshipHarvard UniversityNSF predoctoral fellow; Biophysics,Professor Guido Guidotti, advisor
FellowshipUniversity of OregonAnna Fuller Fund Fellow, American Cancer Society Fellow; Post-doctoral fellow with Professor Edward Herbert

Awards
Name of Award/HonorAwarding Organization
Osborn Award for Excellence in Graduate Student Teaching Univ of Conn Health Center
Inducted into CASECASE
Watkins Professorship, Department of Chemistry Wichita State University
Janice and Rodney Reynolds Professor of Neurobiology
Merit Award DK-32949
Elizabeth Dunaway-Burham FellowDartmouth Medical School
C.H. Li Memorial Lectureship, Berkeley, CA
Merit Award DK-32949
Ernst Oppenheimer Memorial AwardEndocrine Society
Vincent Du Vigneaud Award for Peptide Research by Young Investigators.
Peptides; membrane protein trafficking; cuproenzymes; neurons; pituitary Peptides seem to have preceded the 'classical' transmitters as the nervous system developed - creatures like Hydra and Drosophila utilize peptides to control key developmental decisions. Beginning with our work on proopiomelanocortin and the coordinate biosynthesis of ACTH and the opioid peptide beta-endorphin, I have been fascinated with the effort that neurons and endocrine cells devote to the biosynthesis, storage and regulated secretion of peptides. As we have learned more about the specific enzymes involved in the biosynthesis of peptides, we have learned important questions to ask about how these enzymes function in cells and in the whole animal. We have focused a great deal of our effort on the process of peptide amidation. This seemingly trivial modification to the COOH-terminus of peptides often turns out to be essential for their biological activity. Hypothalamic peptides like oxytocin and vasopressin along with neuropeptides like substance P and gastrointestinal mediators like gastrin must be amidated in order to affect their target tissues. By purifying an enzyme capable of converting peptidylglycine precursors into amidated products, we were then able to clone a cDNA encoding this enzyme. To our surprise, this modification requires the sequential action of two enzymes, a monooxygenase and a lyase. The enzyme has been named PAM, short for peptidylglycine alpha-amidating monooxygenase. The monooxygenase itself is called PHM, short for peptidylglycine alpha-hydroxylating monooxygenase, and the lyase is called PAL, short for peptidyl-alpha-hydroxylglycine alpha-amidating lyase. PHM uses ascorbic acid (vitamin C) to reduce the two copper atoms that are bound to its catalytic core and molecular oxygen is the final component of the reaction. PAL also requires a metal ion, zinc, for activity. With its need for copper, zinc and ascorbate, PAM function is sensitive to genetic and environmental factors. We have expressed the bifunctional PAM protein in soluble and membrane forms and have purified milligram amounts of the two separate catalytic domains, PHM and PAL. With Dr. Mario Amzel, we were able to deduce the crystal structures for PHM and for PAL. One copper binds to the N-terminal domain of the PHM catalytic core and the other to the C-terminal domain; how both sites contribute to the reaction is not yet clear. The beta-propeller structure of PAL constrains PHM to a location near the granule membrane, with important functional implications. Along with structure function studies, our current efforts are aimed at understanding what the cells that use PAM have to do in order to provide copper to the enzyme. Copper is an extremely toxic metal and specific pumps and chaperones are used to deliver it to the proteins that need it. PAM knockout mice do not survive beyond mid-gestation; PAM heterozygous mice are viable, but exhibit increased anxiety-like behavior, an inability to thermoregulate and increased seizure sensitivity. Many of these deficits are mimicked in mildly copper-deficient wildtype mice and ameliorated by providing supplementary dietary copper to PAM heterozygous mice. We are using these animal models to understand the role of PAM in coping with copper availability and are collaborating with our clinical colleagues to see if mild copper deficiency occurs in patient populations. In addition to its catalytic domains, PAM has non-catalytic regions. In particular, the transmembrane domain and cytosolic domain of PAM need not be present for the enzyme to function. The role of these non-catalytic domains seems to be in getting PAM to the right place in the cell so that it can do its job. In particular, the cytosolic domain is essential for targeting PAM to the secretory granules of pituitary endocrine cells and for guiding PAM protein that has reached the cell surface back into secretory granules following internalization. We recently found that a gamma-secretase-like cleavage releases a soluble cytosolic domain fragment of PAM that enters the nucleus and alters gene expression. This adds a new dimension to our studies of PAM and we are in seach of the underlying mechanism. A PAM cytosolic domain interactor protein of great interest is kalirin, a member of the Dbl family of GDP/GTP exchange factors for small GTP binding proteins of the Rho sub-family. The cytosolic domain of PAM binds to the spectrin-like repeat region of kalirin. This region of Kalirin is followed by a Dbl homology or DH domain, and a PH domain. Kalirin occurs naturally in a variety of isoforms and this first DH/PH domain can be followed by a PDZ-binding motif (Kalirin-7), an SH3 motif (Kalirin-8), another DH/PH domain (Kalirin-9) or another DH/PH domain and a putative serine/threonine protein kinase (Kalirin-12). The various isoforms of kalirin are expressed at different times during development and are localized to different regions of the cell. Mice engineered to lack expression of Kalirin globally or only in pituitary corticotropes are being used to identify the major roles of Kalirin in the pituitary and in the nervous system.

Not accepting students for Lab Rotations at this time

Lab Rotation Projects
Project 1: Isolating multivesicular bodies/recycling endosomes.
Following exocytosis, secretory granule membrane proteins can be re-used or degraded; the choice is regulated by ubiquitination and phosphorylation. Pituitary cells incubated with antibody to a secretory granule membrane protein (PAM) will be stimulated with secretagogue and the subcellular compartments containing the internalized antibody (and thus PAM that has visited the cell surface) will be isolated and characterized. Cell culture, Western analyses, subcellular fractionation techniques.

Project 2: Routing of PAM in neurons.
PAM is a large dense core vesicle integral membrane protein which amidates bioactive peptides. The intracellular routing of PAM is controlled largely by its 80-residue cytosolic domain, which is known to undergo phosphorylation at several residues. Although the trafficking of PAM in endocrine cells has been studied in detail, little is know about how PAM travels to dendrites and to axon terminals. Primary neuronal cultures, fluorescence microscopy, enzyme assays.

Project 3: Search for Kalirin-7 interactors.
Rho GDP-GTP exchange factors (GEFs) play critical roles in regulating the actin cytoskeleton. Kalirin, a GEF specific for RhoG and for Rac1, interacts with secretory granule membrane proteins and with components of the post-synaptic density. Factors regulating the activity and localization of Kalirin-7 are poorly understood. Structure/function studies have revealed an important role for the spectrin-repeat region but the key interactors have not yet been identified.

Journal Articles

Book Chapters

  • Peptidylglycine alpha-Amidating Monooxygenase (PAM)
    Vishwanatha KS, Mains RE, Eipper BA Handbook of Biologically Active Peptides 2013 Jan;Chapter 244
  • Peptides
    Mains RE, Eipper BA Basic Neurochemistry 2011 Jan;423-439
  • Neuropeptides: Synthesis and storage.
    Sobota JA, Eipper BA, Mains RE Encyclopedia of Neuroscience, Vol. 6 2007 Jan;829-836
  • Peptides
    Mains RE, Eipper BA Basic Neurochemistry, 7th Edition 2006 Jan;317-332
  • Peptides
    Mains RE, Eipper BA Basic Neurochemistry 2006 Jan;317-332
  • Amidation
    Bell, J, Eipper, BA, Mains, RE Encyclopedia of Endocrine Diseases, Vol 1 2004 Jan;188-191
  • Peptide Amidation.
    Niciu MJ, Mains RE and Eipper BA Encyclopedia of Biological Chemistry, Vol.3 2004 Jan;226-230
  • Peptidylglycine alpha-Amidating Monooxygenase (PAM).
    Steveson,RC, Bell,J, Mains,RE, Eipper,BA John Wiley Encyclopedia of Molecular Medicine, Vol 4 2002 Jan;2438-2441
  • Proopiomelanocortin synthesis and cell-specific processing
    Mains, RE, Eipper, BA Handbook of Physiology. Section 7: The Endocrine System, Volume IV: Coping with the Environment: Neural and Endocrine Mechanisms 2000 Jan;85-101
  • Neuropeptide Precursors.
    Eipper,BA and Mains,RE Elsevier’s Encyclopedia of Neuroscience 1999 Jan;1422-1423
  • Neuropeptide precursors.
    Eipper, B.A. and Mains, R.E. The Encyclopedia of Neuroscience 1997 Jan;
  • Cellular and molecular approaches to bioactive peptide processing.
    Mains,RE, Dickerson,IM, May,V, Stoffers,DA, Ouafik,L'H, Perkins,SN, Husten,EJ, Eipper,BA Frontiers in neuroendocrinology 1990 Jan;52-89
  • Tissue-specific expression of membrance and soluble forms of peptidyl-glycine alpha-amidating monooxygenase.
    Stoffers,DA, Eipper,BA Alfred Benzon Symposium 29, Neuropeptides and their Receptors 1990 Jan;152-165
  • Alternative mRNA splicing generates multiple forms of peptidyl-glycine alpha-amidating monooxygenase in rat atrium.
    Stoffers, D A; Green, C B; Eipper, B A Proceedings of the National Academy of Sciences of the United States of America 1989 Jan;86(2):735-9
  • Cotranslational and posttranslational processing in the production of bioactive peptides.
    Eipper,BA, May,V, Cullen,EI, Sato,SM, Murthy,ASN, Mains,RE Psychopharmacology: The Third Generation of Progress 1987 Jan;386-400
  • Synthesis and secretion of ACTH, beta-endorphin, and related peptides.
    Mains,RE, Eipper,BA Neurosecretion and Brain Peptides 1981 Jan;35-47
  • Basal secretion of peptides derived from the ACTH/endorphin precursor by rat pituitary cells in culture.
    Eipper,BA, Mains,RE Brain and Pituitary Peptides 1980 Jan;12-20
  • Coordinate synthesis and release of corticotropin and endorphin.
    Mains,RE, Eipper,BA Endorphins in Mental Health Research 1978 Jan;143-156
  • Studies on the common precursor to ACTH and endorphin.
    Mains,RE, Eipper,BA Endorphins '78 1978 Jan;79-126

Reviews

  • Neuropeptide Synthesis and Storage.
    Sobota JA, Eipper BA, Mains RE Encyc of Neurosci 2009 Jan;6829-836
  • Book Review: Posttranslational Modifications of Proteins: Expanding Nature’s Inventory by Christopher T. Walsh.
    Eipper BA Quarterly Review of Biology 2008 Jan;83403
  • Kalirin: a dual Rho guanine nucleotide exchange factor that is so much more than the sum of its many parts.
    Rabiner, Chana A; Mains, Richard E; Eipper, Betty A The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 2005 Apr;11(2):148-60
  • Kalirin: a dual Rho GEF that’s so much more than the sum of its many parts
    Rabiner CA, Mains RE, Eipper BA The Neuroscientist 2005 Jan;11148-160
  • Regulation of olfactory neurogenesis by amidated neuropeptides.
    Hansel, D E; Eipper, B A; Ronnett, G V Journal of neuroscience research 2001 Oct;66(1):1-7
  • Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing and routing domains.
    Eipper,BA, Milgram,SL, Husten,EJ, Yun,H-Y, Mains,RE Prot Sci 1993 Jan;2489-497
  • The biosynthesis of neuropeptides: peptide alpha-amidation.
    Eipper,BA, Stoffers,DA, Mains,RE Annu Rev Neurosci 1992 Jan;1557-85
  • The role of ascorbate in the biosynthesis of neuroendocrine peptides.
    Eipper,BA, Mains,RE Am J Clin Nutr 1991 Jan;541153S-1156S
  • Peptide alpha-amidation.
    Eipper,BA, Mains,RE Annu Rev Physiol 1988 Jan;50333-344
  • Strategies for the biosynthesis of bioactive peptides.
    Mains,RE, Eipper,BA, Glembotski,CC, Dores,RM Trends Neurosci 1983 Jan;6229-235
  • Structure and biosynthesis of pro-adrenocorticotropin/endorphin and related peptides.
    Eipper, B A; Mains, R E Endocrine reviews 1980 Jan;1(1):1-27
Title or AbstractTypeSponsor/EventDate/YearLocation
Copper in the AmygdalaTalkCopper 2012, international symposium2012Alghero, Italy
The Roles of Kalirin Within and Outside of the Nervous SystemTalkUniversity of Barcelona2012Barcelona, Spain
Kalirin - Structure/FunctionTalkNeuroscience Department2012UCHC
Kalirin - spectrin repeats matterTalkMMSB Department Retreat2012
MMSB chalk talk Talk2011MMSB
Structure/Function – Peptide Amidation TalkMMSB Departmental Retreat 2010MMSB
Mixing animal models and protein structure: RhoGEFs at the PSD TalkMMSB Chalk Talk2010
Responsible Conduct in Research – for UCHC post-docs TalkOrganized by Dr. Gerry Maxwell2010UCHC