Signals are transmitted from one neuron to another at the synapse, a key element for information processing and storage. Glutamate is the prevalent 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. Activation of Ca2+ permeable NMDA-type glutamate receptors and the subsequent rise of postsynaptic Ca2+ triggers LTP via the Ca2+/calmodulin-dependent protein kinase CaMKII and the cAMP-dependent protein kinase PKA. 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 (Leonard et al., 1999; 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 and the AMPA-type glutamate receptor subunit GluA1assemble signaling complexes at the postsynaptic site that controls Cav1.2 activity and GluA1 accumulation via phosphorylation by PKA (Davare et al., 2001; Joiner et al., 2010). These complexes contain the Beta 2 adrenergic receptor, heterotrimeric Gs, adenylyl cyclase, PKA and the antagonistic phosphatase PP2A and PP2B/calcineurin. Assembly of these components into one complex explains for the first time how signaling by receptors acting through cAMP and PKA can be very fast, spatially restricted, and specific. They provide the very first glimpse into the molecular basis of how norepinephrine increases the acuity of our sensory systems and enhances learning under emotional conditions.

Glutamate receptors interact with structural proteins such as PSD-95 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. Synaptic plasticity is critical for learning including fear conditioning as occurring during posttraumatic stress disorder (PTSD). We study the role of these signaling events in fear conditioning and other learning behaviors. Overstimulation of glutamate receptors triggers neurological damage during stroke, epilepsy, and Alzheimer's disease. We are investigating the role of these and other similar interactions under physiological and related neuropathological conditions. We develop peptides that are membrane-permeant, specifically disruption certain interactions, and thus might be beneficial in the treatment of stroke, epilepsy, PTSD, and other neurological and mental diseases.

Selected Publications

Books

J. W. Hell and M. D. Ehlers (2008): Structural and Functional Organization of the Synapse. Springer, Heidelberg. Contributors include G. Augustine, B. Barres, D. Bergles, W. Catterall, D. Choquet, R. Edwards, M. Ehlers, A. El-Husseini, C. Garner, K. Harris, M. Kennedy, J. Lisman, K. Martin, M. Mayer, J. McNamara, P. McPherson, B. Sabatini, M. Salter, J. K. Shen, R. Simon, K. Swoboda, S. Traynelis, G. Turrigiano, M. Welsh, and R. Wenthold.

Articles

J. W. Hell, P. R. Maycox, H. Stadler and R. Jahn (1988): Uptake of GABA by rat brain synaptic vesicles isolated by a new procedure. EMBO J 7, 3023-3029.

J. W. Hell, C. T. Yokoyama, L. J. Breeze, C. Chavkin and W. A. Catterall (1995): Phosphorylation of presynaptic and postsynaptic calcium channels by cAMP-dependent protein kinase in hippocampal neurons. EMBO J 14, 3036-3044.

A. S. Leonard and J. W. Hell (1997): Cyclic AMP-dependent protein kinase and protein kinase C phosphorylate N-methyl-D-aspartate receptors at different sites. J Biol Chem 272, 12107-12115.

A. S. Leonard, M. A. Davare, M. C. Horne, C. C. Garner, and J. W. Hell (1998): SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic receptor GluR1 subunits. J Biol Chem 273, 19518-19524.

A. S. Leonard, I. A. Lim, D. E. Hemsworth, M. C. Horne, and J. W. Hell (1999): Calcium-calmodulin-dependent protein kinase II is associated with the N-methyl-D- aspartate receptor. Proc Natl Acad Sci USA 96, 3239-3244 (member-independent submission by track II).

M. A. Davare, F. Dong, C. S. Rubin, and J. W. Hell (1999): The A-kinase anchor protein MAP2B and cAMP-dependent protein kinase are associated with class C L-type calcium channels in neurons. J Biol Chem 274, 30280-30287.

M. A. Davare, M. C. Horne, and J. W. Hell (2000): Protein phosphatase PP2A is associated with class C L-type calcium channels and antagonizes channel phosphorylation by cAMP-dependent protein kinase. J Biol Chem 275, 39710-39717.

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

M. A. Davare, V. Avdonin, D. D. Hall, E. M. Peden, A. Burette, R. J. Weinberg, M. C. Horne, T. Hoshi, and J. W. Hell (2001): A Beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav2.1. Science 293, 98-101. [This Week in Science, Science 293, 11 (2001); Perspectives, Science 293, 62-63 (2001); Letters, Science 293, 2204-2205; Full Highlights, Nat Neurosci Rev 2, 535]

I. A. Lim, D.D. Hall, and J.W. Hell (2002): Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102. J Biol Chem 277, 21697-21711.

A. S. Leonard, K.-U.Bayer, M. A. Merrill, I. A. Lim, M. A. Shea, H. Schulman, and J. W. Hell (2002): Regulation of calcium/calmodulin-dependent protein kinase II docking to N-methyl-D-aspartate receptors by calcium/calmodulin and -actinin. J Biol Chem 277, 48441-48448.

G. K. Seabold, A. Burette, I. A. Lim, R. J. Weinberg, and J. W. Hell (2003): Interaction of the tyrosine kinase Pyk2 with the N-methyl-D-aspartate receptor complex via the Src homology 3 domains of PSD-95 and SAP102. J Biol Chem 278, 15040-15048.

M. A. Davare and J. W. Hell (2003): Increased phosphorylation of the neuronal L-type Ca2+ channel Cav1.2 during aging. Proc Natl Acad Sci USA 100, 16018-16023.

K. S. Christopherson, E. M. Ullian, C. C. A. Stokes, C. E. Mullowney, J. W. Hell, A. Agah, J. Lawler, D. F. Mosher, P. Bornstein, and B. A. Barres (2005): Thrombospondins are astrocyte-secreted proteins that promote synaptogenesis. Cell 120, 421-433.

M. A. Merrill, Y. Chen, S. Strack, and J. W. Hell (2005): Activity-driven postsynaptic translocation of CaMKII. Trends Pharmacol. Sci. 26, 645-653.

D. D. Hall, J. A. Feekes, A. S. Arachchige Don, M. Shi, J. Hamid, L. Chen, S. Strack, G. W. Zamponi, M. C. Horne, and J. W. Hell (2006): Binding of protein phosphatase 2A next to S1928, the main PKA site of the L-type calcium channel Cav1.2, is critical for S1928 dephosphorylation. Biochem 45, 3448-3459.

D. D. Hall, M. A. Davare, M. Shi, M. L. Allen, M. Weisenhaus, G. S. McKnight, and J. W. Hell (2007): Critical role of PKA anchoring to the L-type calcium channel Cav1.2 via AKAP150 in neurons. Biochem 46, 1635-1646.

M. A. Merrill, Z. Malik, Z. Akyol, J. A. Bartos, A. S. Leonard, A. Hudmon, M. A. Shea, and J. W. Hell (2007): Displacement of -actinin from the NMDA receptor NR1 C0 domain by Ca2+/calmodulin promotes CaMKII binding. Biochem 46, 8485-8497 (1 of 4 “Hot Articles” in Biochem July 2007).

Y. Lu, M. L. Allen, A. R. Halt, M. Weisenhaus, R. F. Dallapiazza, D. D. Hall, Y. M. Usachev, G. S. McKnight, and J.W. Hell (2007): Age-dependent requirement of AKAP150-anchored PKA and GluR2-lacking AMPA receptors in LTP. EMBO J 26, 4879-4890.

Y. Chen, B. Stevens, J. Chang, J. Milbrandt, B. A. Barres, and J. W. Hell (2008): NS21: Re-defined and modified supplement B27 for neuronal cultures. J Neurosci Meth 171, 239-247. [Nature News, Nature 459, 19 (2009)]

Y. Lu, M. Zhang, I. A. Lim, D. D. Hall, M. L. Allen, Y. Medvedeva, G. S. McKnight, Y. M. Usachev, and J.W. Hell (2008): AKAP150-anchored PKA activity is important for LTD during its induction phase. J Physiol 586, 4155-4164.

M. A. Joiner, M.-F. Lise, E. Y. Yuen, A. Y. F. Kam, D. D. Hall, Z. Malik, H. Qian, Y. Chen, J. D. Ulrich, A. C. Burrette, R. J. Weinberg, P.-Y. Law, A. El-Husseini, Z. Yan, and J. W. Hell (2009): Assembly of a 2 adrenergic receptor – GluR1 signaling complex for localized cAMP signaling. EMBO J. in press.

J. A. Bartos, H. Li, M. A. Beazely, J. D. Ulrich, Y. Chen, J. F. MacDonald, and J. W. Hell (2009): Postsynaptic clustering and activation of Pyk2 by PSD-95. J Neurosci. in press.

J. W. Hell (2009): Hooked on the D3 Receptor: CaMKII’s New Addiction. Neuron 61, 335-336.

S. Dai, D. D. Hall, and J. W. Hell (2009): Regulation of Ion Channels by Locally Controlled Phosphorylation. Invited review. Physiol. Rev. 89, 411-452.

See: Complete List of Publications