Johannes W Hell
University of California-Davis, CA·Neuroscience
Norepinephrine is a brain chemical that keeps us alert and attentive. It acts in part at synapses that use glutamate, the brain's main excitatory signal, where it can strengthen communication between neurons.
- Fields
Neuroscience
Pharmacology
Biochemistry
- Topics
norepinephrine
noradrenaline
beta-2 adrenergic receptor
- Grants
- 2 known grants, through Jul 2027
What they work on
- Test whether norepinephrine taken into neurons by the transporters OCT3 and PMAT activates internal β2ARs to drive GluA1 phosphorylation, AMPAR surface delivery and LTP, using inhibitors, knockout mice, immunoblotting and immunofluorescence.
- Test whether the cAMP-degrading enzyme PDE4A5, linked to the AMPAR complex via PSD-95, limits β2AR-PKA upregulation of AMPARs, by displacing it with polypeptides and measuring GluA1 phosphorylation, surface levels and synaptic currents.
- Map the binding sites between AMPARs and the CaV1.2 calcium channel and test, with mutations, acute peptides and live imaging, how this supercomplex affects calcium entry into dendritic spines and GluA1 surface insertion.
- Test whether amyloid beta oligomers increase CaV1.2 activity in dendrites and spines through β2AR and S1928 phosphorylation, and whether blocking this with drugs or S1928A knock-in mice reduces neurotoxicity.
- Determine whether amyloid beta-β2AR-S1928 signaling adds calcium-permeable AMPARs and alters LTP and LTD, using live imaging, electrophysiology and S1928A mice crossed with the 5xFAD Alzheimer's model.
More about the research
In these synapses, norepinephrine's main receptor, the beta-2 adrenergic receptor (β2AR), sits in tight protein complexes with two key partners. One is the AMPA receptor (AMPAR), which carries fast excitatory signals. The other is CaV1.2, a calcium channel that lets calcium into neurons. The complexes also hold the machinery that makes and responds to cAMP, a messenger molecule inside cells, including PKA, an enzyme that adds phosphate tags to proteins. Together, the lab's projects ask how this local signaling controls synaptic strength in the healthy brain, and how amyloid beta, the peptide that builds up in Alzheimer's disease, hijacks it.
Why it matters
Faulty norepinephrine signaling, glutamate receptors and CaV1.2 channels are linked to Alzheimer's disease, PTSD, schizophrenia and ADHD. Mapping the specific protein contacts in these synaptic complexes could reveal new, selective drug targets. Peptides that block one interaction without disturbing others could serve as such tools. An early amyloid beta-β2AR-CaV1.2 step could also be a target for early intervention in Alzheimer's disease.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Jason D Shepherd
University of Utah, UT·Neuroscience
Test whether LTP increases Arc protein in dendrites and its assembly into virus-like capsids, using live imaging of neurons.
Martin Hruska
West Virginia University, WV·Neuroscience
Test how acute amyloid-beta affects PSD-95 stability in spines with different numbers of nanomodules. Use live-cell STED super-resolution imaging, with CRISPR tags on the neurons' own PSD-95 and AMPA receptors.
Kim Dore
University of California-San Diego, CA·Neuroscience
Measure PSD-95 palmitoylation, the fatty tag that anchors this scaffold protein in synapses, across brain regions differently affected by Alzheimer's in APP/PS1 model mice and postmortem human brain samples.
The school
University of California-Davis: 49 labs on PI Pages, $1.0B a year on research, 647 research doctorates a year.
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