Signals are transmitted between neurons at synapses. Glutamate, the prevailing neurotransmitter in the brain, 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 constitutes the physiological basis of learning and memory. 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 kinase Src. We are studying the spatio-temporal regulation of these kinases at postsynaptic sites and how they control glutamate receptors.

For fast and specific signaling kinases are anchored next to their substrates. We discovered that CaMKII directly interacts 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 the L-type Ca2+ channel Cav1.2 assembles 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 b2 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.

We combine modern molecular/cell biological, protein biochemical, immunohistochemical, and electrophysiological methods to study synaptic plasticity. Overstimulation of glutamate receptors triggers neurological damage during stroke and epilepsy, and L-type Ca2+ channels play a role in the etiology of Alzheimer's disease. Our research on the molecular basis of these neuropathological conditions contributes to the development of treatments for these diseases.

Image: Dr. Hell with one of his mutant NMDA receptor mice, that seems to have to his surprise no facial hair.