Johannes Hell, Ph.D.

 Johannes  Hell, Ph.D.

Position

  • Professor
  • Pharmacology

Contact

Postsynaptic Signaling Mechanisms Including Signaling Complexes Formed by Glutamate Receptor and Ca Channels

Research Summary

Spatio-temporal organization of postsynaptic signaling

The synapse mediates signal transmission from one neuron to another, data processing, and information storage. It incorporates these different functions into a tiny structure of about 1 micrometer in diameter. This functionality requires a highly complex yet precisely organized assembly of proteins in which crucial functional interactions depend on the exact spatial alignment of the interacting molecules. Our ultimate goal is to understand this relationship between structure and function, between position and effect, of key proteins in postsynaptic signaling. Achieving this goal is critical for understanding synaptic function and its modulation. It is also crucial for development of therapeutic strategies for a number of neurological disorders. 

Glutamate is the prevalent neurotransmitter in the brain. 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 by opening their ion-conducting pores. In addition to these ligand-gated ion channels, voltage gated ion channels shape the postsynaptic response and its plasticity. We study the molecular mechanisms that govern the postsynaptic localization of the main two glutamate receptors, AMPARs and NMDARs, and the voltage gated L-type Ca2+ channel, Cav1.2. We also investigate the regulation of these channels by different protein kinases and phosphatases, which mediate short and long term modulations of postsynaptic responses.

Neurotransmission at a given synapse is typically very stable. However, a short episode (1 s) of high frequency stimulation (10-100 Hz) causes a long-lasting increase in the strength of the neurotransmission at the stimulated synapse. This potentiation is called long-term potentiation (LTP) because it can last a lifetime. LTP in the hippocampus and cortex is thought to constitute the physiological basis of learning and memory. On a molecular level, high frequency stimulation leads to Ca2+ influx through the otherwise silent NMDAR and also through Cav1.2. Inside the postsynaptic site, Ca2+ activates the Ca2+- and calmodulin-dependent protein kinase CaMKII.  This kinase modifies several postsynaptic proteins by phosphorylation, an event that leads to an increase in the functional availability of AMPARs at this synapse. It is largely unknown, which proteins mediate this increase in AMPAR activity upon their phosphorylation and how but it must involve an increase in AMPAR number by modulation of molecular anchoring mechanisms for AMPARs at postsynaptic sites.  We study these anchoring mechanisms and their modifications by Ca2+ influx, calmodulin, and CaMKII, and by b adrenergic signaling via cAMP-dependent protein kinase (PKA).

We use state of the art protein biochemical, molecular and cell biological, electrophysiological and behavioral methods to evaluate the interplay of these proteins and their physiological (LTP) and behavioral (learning) effects. Our research is relevant for numerous neurological and mental disorders. We have a specific interest in epilepsy, stroke, Alzheimer’s disease, and posttraumatic stress disorder.

Select Publications

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 b2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2.  Science 293, 98-101.

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 a-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.

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 a-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. 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.

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.

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

M. A. Joiner, M.-F. Lise, E. Y. Yuen, A. Y. F. Kam, M. Zhang, D. D. Hall, Z. Malik, H. Qian, Y. Chen, J. D. Ulrich, A. C. Burette, R. J.  Weinberg, P.-Y. Law, A. El-Husseini, Z. Yan, and J. W. Hell (2010): Assembly of a b2 adrenergic receptor – GluR1 signaling complex for localized cAMP signaling. EMBO J 29, 482-495.

J. A. Bartos, H. Li, M. A. Beazely, J. D. Ulrich, Y. Chen, J. F. MacDonald, and J. W. Hell (2010): Postsynaptic clustering and activation of Pyk2 by PSD-95.  J Neurosci 30, 449-463.

H. Xu, K. S. Ginsburg, D. D. Hall, M. Zimmermann, I. S. Stein, M. Zhang, S. Tandan, J. A. Hill, M. C. Horne, D. M. Bers, and J. W. Hell (2010): Targeting of protein phosphatases PP2A and PP2B to the C-terminus of the L-type calcium channel Cav1.2. Biochem 49, 10298-10307.

J. W. Hell (2010): Perspective: b-adrenergic regulation of the L-type Ca2+ channel Cav1.2 by PKA rekindles excitement. Sci Signal 3, pe33.

Y. Lu, X. Zha, E. Y. Kim, S. Schachtele, M. E. Dailey, D. D. Hall, S. Strack, S. H. Green, D. A. Hoffman, and J.W. Hell: A kinase anchor protein 150-associated protein kinase A limits dendritic spine density. J Biol Chem 286, 26496-26506.

AR Halt*, RF Dallapiazza*, Y Zhou, IS Stein, H Qian, S Juntti, S Wojcik, N Brose, AJ Silva, and JW Hell (2012): CaMKII binding to GluN2B is critical during memory consolidation. EMBO J 31, 1203-1216 (*the two first-authors made equal contributions).

H Qian, L Matt, M Zhang, M Nguyen, T Patriarchi, OM Koval, ME Anderson, K He, H-K Lee, and JW Hell (2012): b2 AR supports prolonged theta tetanus-induced LTP. J Neurophysiol 107, 2703-2712.

TI Apak Evans, JW Hell, and MA Shea (2011): Thermodynamic linkage between calmodulin domains binding calcium and contiguous sites in the C-terminal tail of Cav1.2. Biophys Chem 159, 172-187.

AM Hamilton, WC Oh, H Vega-Ramirez, IS Stein, JW Hell, GN Patrick, and K Zito (2012): Activity-dependent growth of new dendritic spines is regulated by the proteasome.  Neuron  74, 1023-1030.

J Xu, P Kurup, JA Bartos, T Patriarchi, JW Hell*, and PJ Lombroso* (2012): STriatal-enriched protein tyrosine phosphatase (STEP) regulates Pyk2 activity. J Biol Chem 287, 20942-20956.  (*co-corresponding authors).

D Wang, Q Fu, Y Zhou, B Xu, Q Shi, B Igwe, L Matt, JW Hell, EV.Wisel, S Oddo, YK Xiang  (2013): β2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer’s disease models. J Biol Chem 288, 10298-10307.

L. Matt and J. W. Hell (2013): Have you seen? PKCl: a new player in LTP coming to the rescue of PKCz’s faltering role in LTP? EMBO J. 32, 1348-1349.

DD Hall*, S Dai*, P-Y Tseng*, ZA Malik, M Nguyen, L Matt, K Schnizler, A Shephard, DP Mohapatra, F Tsuruta, RE Dolmetsch, CJ Christel, A Lee, A Burette, RJ Weinberg, and JW Hell (2013): Competition between a-actinin and Ca2+-calmodulin controls surface retention of the L-type Ca2+ channel Cav1.2. Neuron 78, 483-497 (*co-first authors).

L Matt and JW Hell (2014): Have you seen? LTP: GluN2B on the go. EMBO J 33, 781-782.

M Zhang, T Patriarchi, IS Stein, H Qian, L Matt, M Nguyen, YK Xiang, and JW Hell (2013): Adenylyl Cyclase Anchoring by A Kinase Anchor Protein AKAP5 (AKAP79/150) is Important for Postsynaptic b-Adrenergic Signaling. J Biol Chem 288, 17918-17931 (*co-first authors).

FL Núñez-Santana, MM Oh, MD Antion, A Lee, JW.Hell, and JF Disterhoft (2014): Surface L-type Ca2+ channel expression levels are increased in aged hippocampus. Aging Cell 13, 111-120.

JW Hell (2014): CaMKII: claiming center stage in postsynaptic function and organization. Neuron 81, 249-265.

DJ Speca, G Ogata, D Mandikian, HI Bishop, SW Wiler, K Eum, HJ Wenzel, ET Doisy, L Matt, KL Campi, MS Golub, JM Nerbonne, JW Hell, BC Trainor, JT Sack, PA Schwartzkroin, and JS Trimmer (2014): Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability. Genes, Brain and Behavior 13, 394-408.

MF Navedo and JW Hell (2014): Preview: AKAP5 keeps L-type Channels and NFAT on their toes. Cell Rep 7, 1341-1342.

JA Murphy*, IS Stein*, CG Lau, RT Peixoto, TK Aman, N Kaneko, K Aromolaran, JL Saulnier, GK Popescu, B Sabatini, JW Hell**, and RS Zukin** (2014):Phosphorylation of Serine 1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines. J Neurosci 34, 869-879 (*co-first authors; **co-corresponding authors).

Y Zhang*, L Matt*, T Patriarchi*, ZA Malik, D Chowdhury, DK Park, A Renieri, JB Ames**, and JW Hell**(2014): Capping of the N-terminus of PSD-95 by Calmodulin Triggers its Postsynaptic Release. EMBO J 33,1341-1353  (*co-first authors; **co-corresponding authors.

C-Y Chen, L Matt, JW Hell, and MA Rogawski(2014): Perampanel inhibition of AMPAR currents in cultured hippocampal neurons. PLOS One 9, e108021.

IS Stein, MS Donaldson, and JW Hell: CaMKII binding to GluN2B is important for massed spatial learning in the Morris Water Maze. F1000 3, 133.

ZA Malik, SI Stein, MF Navedo and JW Hell (2014): Preview: Mission CaMKIIg: Shuttle calmodulin from membrane to nucleus. Cell 159, 235-237.

 G Atkin, S Moore, Y Lu, RF Nelson, N Tipper, G Rajpal, J Hunt, W Tennant, JW Hell, GG Murphy, and H Paulson (2015): Loss of F-box Only Protein 2 (Fbxo2) disrupts the levels and localization of select NMDA receptor subunits, and promotes aberrant synaptic connectivity. J Neurosci 356165-6178.

K He, M Huertas, SZ Hong, XX Tie, JW Hell, H Shouval, A Kirkwood (2015). Distinct Eligibility Traces for LTP and LTD in Cortical Synapses. Neuron 88, 528-538.

T Patriarchi, H Qian, V Di Biase, ZA Malik, D Chowdhury, JL Price, EA Hammes, OR Buonarati, RE Westenbroek, WA Catterall, F Hofmann, YK Xiang, GG Murphy, C-Y Chen, MF Navedo, and JW Hell (2015): Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the badrenergic receptor.  EMBO J 35, 1330-1345.

[Evaluation as ***, Faculty of 1000 Prime, 21 Apr 2016 http://f1000.com/prime/726306316?ref=ypp]

26 JA Gray, K Zito, and JW Hell (2016): Non-ionotropic signaling by the NMDA receptor: controversy and opportunity. F1000 Reviews (submitted invited Review) 

27 JW Hell (2016) Perspective: Ca2+-permeable AMPARs, PKA, and PP2B Intertwine for LTP and LTD b-adrenergic regulation of the L-type Ca2+ channel Cav1.2 by PKA rekindles excitement. Sci Signal, (submitted invited Perspective).

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.

In addition I have served on various study sections and editorial boards and am a Contributing Member of Faculty of 1000 Biology