Elizabeth Ann Jonas, M.D. Assistant Professor Section of Endocrinology Department of Internal Medicine 333 Cedar Street P.O. Box 208020 New Haven, CT 06520-8020 USA Email: elizabeth.jonas@yale.edu Telephone: (203) 785-5568 Fax:(203) 785-7670

• B.A.(History), Yale University, New Haven, CT, 1982
• M.D., New York University Medical School, New York, NY 1986
  

Research

My laboratory is interested in the release of neurotransmitters and neuropeptides, and how the opening of ion channels on intracellular organelles can greatly potentiate or suppress such release. For example, the presynaptic terminals of neurons have an unusually high density of mitochondria. Using a novel recording technique, we have determined that ion channel activity of mitochondrial membranes increases greatly during synaptic transmission, and that this activity depends on influx of calcium through the plasma membrane and into mitochondria. The increased mitochondrial ion channel activity appears to contribute to short term changes in synaptic memory, and may also be correlated with more prolonged changes in the strength of synaptic transmission.

The Bcl-2 family proteins function as ion channels in the outer mitochondrial membrane and are part of the molecular mechanisms that commit a cell to survive or die in response to environmental signals. We have found that these proteins can also profoundly influence the strength of synaptic transmission and are investigating the hypothesis that they normally regulate the strength, survival or elimination of a particular synaptic connection without influencing the fate of the entire neuron.

In a second project, we are investigating the regulation of neuropeptide release by the insulin receptor tyrosine kinase, and have found that this signaling pathway can trigger release by activating ion channels both in the plasma membrane and on secretory granules. Tyrosine and serine kinases also influence the movement of ion channels between the plasma membrane and intracellular organelles. Regulation of ion channels during neurosecretion by the insulin receptor tyrosine kinase may play a role in neuronal or synaptic longevity.

In the laboratory, we are now continuing to test the hypothesis that regulation of intracellular ion channels influences the strength of synaptic transmission and neuropeptide release and these events in turn regulate the subsequent strength or survival of the synaptic connection. Invertebrate and mammalian model synaptic systems are being used. Electrophysiological techniques, including a novel technique to record ion channels on intracellular organelles in living neurons are combined with immunocytochemistry, proteomics, and calcium imaging to further identify intracellular ion channels and define their roles in synaptic transmission. Our studies may shed light on such important neurobiological topics as learning and memory, hypoxic and traumatic brain injury, and the mechanisms of neurodegenerative diseases.

Selected Recent Publications

1. Jonas, E.A., Knox, R.J., Kaczmarek, L.K., Schwartz, J.H. and Solomon, D.H. Insulin receptor in Aplysia neurons: Characterization, molecular cloning and modulation of ion currents. J. Neurosci. 16:1645-1658 (1996).
2. Knox, R.J., Jonas, E. A., Kao, L.-S., Smith, P.J.S., Connor J,A., and Kaczmarek, L.K. Ca2+-influx and activation of a cation current are coupled to intracellular Ca2+ release in peptidergic neurons of Aplysia. J. Physiol. 494.3: 627-639 (1996).
3. Jonas, E.A. and Kaczmarek, L.K. Regulation of potassium channels by protein kinases. Current Opinion in Neurobiology 6: 318-323 (1996).
4. Jonas, E.A., Knox, R.J., Smith, T. C.M., Wayne, N.L., Connor, J.A. and Kaczmarek, L.K. Regulation by insulin of a unique neuronal Ca2+ pool and neuropeptide secretion. Nature, 385: 343-346 (1997).
5. Jonas, E.A. Headache. In: Neuro-ophthalmology: clinical signs and symptoms (Walsh, T.J., ed.) Baltimore: Williams and Wilkins (1997), p. 465-484.
6. Jonas, E.A, Knox, R.J. and Kaczmarek, L.K. Giga-ohm seals on intracellular membranes: A technique for studying intracellular ion channels in intact cells. Neuron, 19:7-13 (1997).
7. Jonas, E.A. and Kaczmarek, L.K. The inside story: subcellular mechanisms of neuromodulation. In: Beyond Neurotransmission: Neuromodulation and its importance for information processing. Paul S. Katz, ed. Oxford: Oxford Univ. Press (1999), p. 83-120.
8. Jonas, E.A., Buchanan, J. and Kaczmarek, L.K. Prolonged activation of mitochondrial conductances during synaptic transmission. Science, 286: 1347-1350 (1999).
9. Kaczmarek, L.K. and Jonas E.A. Ion channels on intracellular membranes. In: Molecular insights into ion channel biology in health and disease. R.A. Maue Ed. Elsevier, in press.
10. Jonas E.A, Hickman, J.A., Zhang, J., Ivanovska, I., Basanez, G., Zimmerberg, J., Hardwick, J.M., and Kaczmarek, L.K.. Apoptotic and anti-apoptotic proteins produce different patterns of channel activity in presynaptic mitochondria of living neurons. Nature Cell Biol. (under revision).
11. Helm, J., Knox, R.J., Smith, T.C.M., Wayne, N.L., Kaczmarek, L.K. and Jonas E.A. Regulated calcium channel endocytosis by tyrosine kinase inhibitors. In preparation.

Recent Abstracts

1. Jonas, E.A, Knox, R.J. and Kaczmarek, L.K. Giga-ohm seals on intracellular membranes: A technique for studying intracellular ion channels in intact cells. Neuron, 19:7-13 (1997).
2. Jonas, E.A., Buchanan, J. and Kaczmarek, L.K. Prolonged activation of mitochondrial conductances during synaptic transmission. Science, 286: 1347-1350 (1999).
3. Jonas, E.A., Hoit, D., Hickman, J.A., Brandt, T.A., Polster, B.M., Fannjiang, Y., McCarthy, E., Montanez, M., Hardwick, J.M., Kaczmarek, L.K. Modulation of synaptic transmission by the BCL-2 family protein BCL-XL. J. Neurosci., 23: 8423-8431 (2003).
4. Jonas, E A, Hickman, J A, Chachar, M, Polster, B M, Brandt, T A, Fannjiang Y, Ivanovska, I, Basanez, G, Jover, T, Kinnally, K, Zimmerberg, J, Hardwick, JM, Kaczmarek, LK. Pro-apoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living presynaptic terminals. Proc. Natl. Acad. Sci. USA. 101: 13590-13595 (2004).
5. Jonas, E A, Hickman, J A, Hardwick, J M, Kaczmarek, L K. Exposure to hypoxia rapidly induces mitochondrial channel activity within a living synapse. J Biol Chem. 280: 4491-4497, 2005.
6. Bonanni, L., Chachar, M., Li, H., Jones, A., Jover, T., Yakota, N., Ofengeim, D., Flannery, R.J., Miyawaki, T., Cho, C.H., Polster, B.M., Hardwick, J.M., Sensi, S., Zukin, R.S. and Jonas, E.A. Zinc-dependent multiconductance channel activity in mitochondria isolated from ischemic brain. J. Neurosci. 26: 6851-6862 (2006).
7. Jonas, EA. Synaptic apoptosis: The life and death of the synapse. Molecular interventions 6: 208-222 (2006).