Johannes W. Hell, Ph.D.

Johannes W. Hell, Ph.D.
Professor
Ph.D. (biochemistry)
University of Munich, 1990
E-mail: johannes-hell@uiowa.edu
Office: 2-512 BSB
Phone: (319) 384-4732

Molecular Basis of Synaptic Plasticity

Signals are transmitted from one neuron to another at the synapse, a key element for information processing and storage. Glutamate is an important neurotransmitter in the brain and spinal cord. It is released from the presynaptic site upon depolarization and opens glutamate receptors at the postsynaptic site. These receptors are ligand-gated ion channels that initiate the excitation of the postsynaptic neuron. High frequency stimulation of a synapse causes a long-lasting increase in its activity known as long-term potentiation (LTP). LTP in the hippocampus and cortex is thought to constitute the physiological basis of learning and memory. A similar phenomenon in the spinal cord, called wind-up, may underlie certain forms of neuropathic pain. Activation of Ca²⁺ permeable NMDA-type glutamate receptors and the subsequent rise of postsynaptic Ca²⁺ triggers LTP via cAMP-dependent protein kinase (PKA), Ca²⁺/calmodulin-dependent protein kinase (CaMKII), and the tyrosine kinases Src and Pyk 2. We are studying the spatio-temporal regulation of these kinases at postsynaptic sites and how they control glutamate receptors.

A prerequisite for efficient and specific signaling is that kinases are anchored next to their substrates. Until recently, little was known about anchoring of any kinase at postsynaptic sites. We discovered that CaMKII directly interacts in a complex manner with NMDA receptors, which serve as postsynaptic docking sites for CaMKII (Bayer et al., 2001). This interaction places CaMKII at a strategically ideal location where it is most efficiently activated by NMDA receptor-mediated Ca²⁺ influx. We also found that class C L-type Ca²⁺ channel assemble a large signaling complex ("signalosome") at the postsynaptic site that controls channel activity via phosphorylation by PKA. This signalosome is the first of its kind and includes the beta-2 adrenergic receptor, GS, adenylyl cyclase, PKA and the antagonistic phosphatase PP2A (Davare et al., 2001). Assembly of these components into one complex explains for the first time how signaling by receptors acting through cAMP and PKA can be fast and specific.

Glutamate receptors interact with structural proteins such as PSD-95/SAP90 and alpha-actinin that regulate their postsynaptic localization and function. We are investigating whether phosphorylation alters the interaction of glutamate receptors with those structural proteins. Regulation of these interactions controls the molecular architecture of postsynaptic sites. Because maintenance of LTP involves restructuring of synaptic connections, it is crucial to understand the molecular reorganization of synapses during LTP.

We combine modern molecular/cell biological, protein biochemical, immunohistochemical, and electrophysiological methods to study the interplay of components in different cellular signaling pathways with each other and with the cytoskeleton. L-type Ca²⁺ channels play a role in the etiology of Alzheimer's disease. Overstimulation of glutamate receptors triggers neurological damage during stroke and epilepsy. Overactivatioin of glutamate receptors in the spinal cord may lead to neuropathic pain. We are investigating the role of these and other similar interactions under physiological and neuropathological conditions. Using peptides modified to be membrane-permeable we evaluate whether disruption of certain interactions leads to specific effects that might be beneficial in the treatment of stroke, epilepsy, and neuropathic pain.

Representative Publications:

Lu, Y., Zhang, M., Lim, I.A., Hall, D.D., Allen, M.L., Medvedeva, Y., McKnight G.S., Usachev, Y.M., and Hell, J.W.: AKAP150-anchored PKA activity is important for LTD during its induction phase. J Physiol, 2008, in press.
Lu, Y., Allen, M.L., Halt, A.R., Weisenhaus, M., Dallapiazza, R.F., Hall, D.D., Usachev, Y.M., McKnight, G.S., and Hell, J.W.: Age-dependent requirement of AKAP150-anchored PKA and GluR2-lacking AMPA receptors in LTP. EMBO J 26:4879-4890, 2007.
Merrill, M.A., Malik, Z., Akyol, Z., Bartos, J.A., Leonard, A.S., Hudmon, A., Shea, M.A., and Hell, J.W.: Displacement of a-actinin from the NMDA receptor NR1 C0 domain by Ca2+/calmodulin promotes CaMKII binding. Biochem 46:8485-8497, 2007.

Davare M.A., Avdonin V., Hall D.D., Peden E.M., Burette A., Weinberg R.J., Horne M.C., Hoshi T. and Hell J.W. A beta-2 adrenergic receptor signaling complex assembled with the Ca²⁺ channel Cav2.1. Science 293:98-101, 2001.

Bayer K.-U., De Koninck P., Leonard A.S., Hell J.W. and Schulman H. Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature 411:801-804, 2001.

Click here to see a list of additional publications

Center and Program affiliations:

Biosciences Program

Interdisciplinary Graduate Program in Neuroscience

Interdisciplinary Graduate Program in Molecular & Cellular Biology

The Medical Scientist Training Program


	Johannes W. Hell, Ph.D. Professor Ph.D. (biochemistry) University of Munich, 1990 E-mail: johannes-hell@uiowa.edu Office: 2-512 BSB Phone: (319) 384-4732
Molecular Basis of Synaptic Plasticity
Signals are transmitted from one neuron to another at the synapse, a key element for information processing and storage. Glutamate is an important neurotransmitter in the brain and spinal cord. It is released from the presynaptic site upon depolarization and opens glutamate receptors at the postsynaptic site. These receptors are ligand-gated ion channels that initiate the excitation of the postsynaptic neuron. High frequency stimulation of a synapse causes a long-lasting increase in its activity known as long-term potentiation (LTP). LTP in the hippocampus and cortex is thought to constitute the physiological basis of learning and memory. A similar phenomenon in the spinal cord, called wind-up, may underlie certain forms of neuropathic pain. Activation of Ca²⁺ permeable NMDA-type glutamate receptors and the subsequent rise of postsynaptic Ca²⁺ triggers LTP via cAMP-dependent protein kinase (PKA), Ca²⁺/calmodulin-dependent protein kinase (CaMKII), and the tyrosine kinases Src and Pyk 2. We are studying the spatio-temporal regulation of these kinases at postsynaptic sites and how they control glutamate receptors. A prerequisite for efficient and specific signaling is that kinases are anchored next to their substrates. Until recently, little was known about anchoring of any kinase at postsynaptic sites. We discovered that CaMKII directly interacts in a complex manner with NMDA receptors, which serve as postsynaptic docking sites for CaMKII (Bayer et al., 2001). This interaction places CaMKII at a strategically ideal location where it is most efficiently activated by NMDA receptor-mediated Ca²⁺ influx. We also found that class C L-type Ca²⁺ channel assemble a large signaling complex ("signalosome") at the postsynaptic site that controls channel activity via phosphorylation by PKA. This signalosome is the first of its kind and includes the beta-2 adrenergic receptor, GS, adenylyl cyclase, PKA and the antagonistic phosphatase PP2A (Davare et al., 2001). Assembly of these components into one complex explains for the first time how signaling by receptors acting through cAMP and PKA can be fast and specific. Glutamate receptors interact with structural proteins such as PSD-95/SAP90 and alpha-actinin that regulate their postsynaptic localization and function. We are investigating whether phosphorylation alters the interaction of glutamate receptors with those structural proteins. Regulation of these interactions controls the molecular architecture of postsynaptic sites. Because maintenance of LTP involves restructuring of synaptic connections, it is crucial to understand the molecular reorganization of synapses during LTP. We combine modern molecular/cell biological, protein biochemical, immunohistochemical, and electrophysiological methods to study the interplay of components in different cellular signaling pathways with each other and with the cytoskeleton. L-type Ca²⁺ channels play a role in the etiology of Alzheimer's disease. Overstimulation of glutamate receptors triggers neurological damage during stroke and epilepsy. Overactivatioin of glutamate receptors in the spinal cord may lead to neuropathic pain. We are investigating the role of these and other similar interactions under physiological and neuropathological conditions. Using peptides modified to be membrane-permeable we evaluate whether disruption of certain interactions leads to specific effects that might be beneficial in the treatment of stroke, epilepsy, and neuropathic pain. Representative Publications: Lu, Y., Zhang, M., Lim, I.A., Hall, D.D., Allen, M.L., Medvedeva, Y., McKnight G.S., Usachev, Y.M., and Hell, J.W.: AKAP150-anchored PKA activity is important for LTD during its induction phase. J Physiol, 2008, in press. Lu, Y., Allen, M.L., Halt, A.R., Weisenhaus, M., Dallapiazza, R.F., Hall, D.D., Usachev, Y.M., McKnight, G.S., and Hell, J.W.: Age-dependent requirement of AKAP150-anchored PKA and GluR2-lacking AMPA receptors in LTP. EMBO J 26:4879-4890, 2007. Merrill, M.A., Malik, Z., Akyol, Z., Bartos, J.A., Leonard, A.S., Hudmon, A., Shea, M.A., and Hell, J.W.: Displacement of a-actinin from the NMDA receptor NR1 C0 domain by Ca2+/calmodulin promotes CaMKII binding. Biochem 46:8485-8497, 2007. Davare M.A., Avdonin V., Hall D.D., Peden E.M., Burette A., Weinberg R.J., Horne M.C., Hoshi T. and Hell J.W. A beta-2 adrenergic receptor signaling complex assembled with the Ca²⁺ channel Cav2.1. Science 293:98-101, 2001. Bayer K.-U., De Koninck P., Leonard A.S., Hell J.W. and Schulman H. Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature 411:801-804, 2001. Click here to see a list of additional publications Center and Program affiliations: Biosciences Program Interdisciplinary Graduate Program in Neuroscience Interdisciplinary Graduate Program in Molecular & Cellular Biology The Medical Scientist Training Program