John P Leonard

    Email Address:
    College: Liberal Arts and Sciences Department: Biological Sciences
    Title: Professor
    Office: 3055B SEL M/C 067 Phone: 9964261
    Participating in the Chancellor’s Undergraduate Research Awards program: Yes

    Research Interest:
    Research Interests: Molecular neurobiology of ion channel function
    My laboratory is focused on neuronal ion channels. We are interested in both neurotransmitter-sensing and voltage-sensing types of channels. Most recent work involves cell surface receptors for glutamate. Glutamate is the major excitatory neurotransmitter in the mammalian brain. When glutamate binds to its receptor, a channel forms between the surface and the cytoplasm of the neuron allowing cationic current to flow. We study these ion channels by expressing them in a relatively simple, single-cell system, the Xenopus frog oocyte, that can then synthesize channels and incorporate them into the surface membrane. Because there are no glutamate receptors present in native oocytes, we control the types of channels that will be studied. It is also possible to alter the mRNA encoding a given subunit before injection to alter the channel structure produced. In this way we hope to find particular regions in different glutamate receptors that are responsible for their functional differences.

    Our general area of interest is in the mechanisms that synapses have to change strength of transmission as a result of prior activation. For example, we have found that one type of glutamate receptor doubles its activity when re-tested after activation of a different type of glutamate receptor. Among the variety of endogenous agents that can cause modulation of neuronal ion channel we have recently chosen to concentrate on protein kinases. Protein kinases add a phosphate group to certain amino acid residues on the polypeptide chain. Such phosphorylation often modulates function of receptors just as it can for enzymes.

    In a particularly robust example of phosphorylation causing neuromodulation, we have found that the activity of one type of glutamate receptor at a glutamatergic synapse could be changed by activity of another type at the same synapse. Selective activation of metabotropic glutamate receptors could change subsequent response at the NMDA subtype of glutamate receptors. This greater than doubling of NMDA receptor current is mediated by activators of protein kinase type C (PKC). NMDA receptors require 2 types of subunits, NR1 and NR2, to bind both glutamate (NR2) and co-agonist glycine (NR1). There are 4 types of NR2 subunits (NR2A-D) found in different NMDA receptors, each with its own influence on functional properties. When the NR2A or NR2B subunit is co-expressed with the NR1 subunit, PKC dramatically increases the current through the receptor. On the other hand, when either the NR2C or NR2D subunit is co-expressed with the glycine binding subunit zeta-1, it prevents PKC from potentiating the receptor's current flow. Expression of point mutations at potential PKC phosphorylation sites present in NR2A and NR2B but absent in NR2C and NR2D have allowed us to identify 2 serine residues controlling direct action of PKC on NMDA receptors. There are also indirect actions of PKC via tyrosine kinases that remain to be studied. Currently we are constructing a knock-in mouse containing NR2A receptors with key phosphorylation sites eliminated. This will allow us to test the importance of these sites to natural physiology and ultimately, behavior of the whole animal.

    Minimum time commitment in hours per week: 9

    Qualifications of a Student:
    Minimum GPA 3.5, Honors College students preferred. Sophomores and Juniors have longer opportunity to use newly developed skills. Seniors have less time to develop, especially do not take second semester seniors into the laboratory.

    Brief Summary of what is expected from the student:
    To work dilligently and carefully under the supervision of a graduate student on mouse behavioral projects. Reliabilty and congeniality are essential.

    NOTE: This researcher is currently not accepting applications for the Undergraduate Research Experience program.

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