Regulation of neuronal ion channels: Dr. Bowie has shown for the first time that a ligand-gated ion-channel can also be co-activated by external ions. Furthermore, he has shown that this novel gating behavior is unique to Kainite receptors and consequently, a novel pharmacological site has been identified for drug development (Nat Struct Mol Biol, 2013; 9:1054-1061). The Bowie lab has also shown a direct link between metabolism in brain cells and their ability to signal information via reactive oxygen species. This relates to the idea that a ketogenic diet can control seizures and treat epilepsy (Nat Commun. 2014; 5:3168).
Quantitative light microscopy: Dr. Brown published a paper showing that by measuring the activation of the serine/threonine kinase Akt she could demonstrate Forster Resonance Energy Transfer (FRET) (Nat Prot 2013; 8, 265-281). Furthermore, she has shown that by measuring the point spread function it is possible to determine confocal microscope resolution, essential for quality control (Nat Prot 2011; 6(12):1929-41).
Loss and enhancement of synaptic strength: Synaptic Dr. Haghighi has shown that the loss of postsynaptic rapamycin TOR disrupts a retrograde compensatory enhancement in neurotransmitter release and has suggested that cap-dependent translation under the control of TOR plays a critical role in establishing the activity dependent homeostatic response at the neuromuscular junction (Neuron 2012; 74: 166-178). He has also demonstrated that the loss of function of a micro RNA cluster (mir-310) leads to an enhancement of synaptic strength at the neuromuscular junction stemming from an increase in presynaptic calcium influx (Neuron 2010; 68:879-893).
Activation and localization of CFTR: Dr. Hanrahan has found that muscarinic receptor agonists can activate CFTR through parallel PKA and Src/Pyk2 tyrosine kinase pathways (J. Biol Chem 2013; 288(30):21981-23). He has also shown that CFTR is present and functional in mucin granules isolated from airway epithelial cells and CFTR-deficient cells have abnormal mucus (Am. J. Respir Cell Mol Biol 2013; 49:511-516)
Domain folding and quality control: Dr. Lukacs has formulated the cooperative domain folding/unfolding mechanism of CFTR showing two primary folding steps that synergistically disrupt coupled domain folding of ∆F508-CFTR (Cell, 2012; 148:150-163). He went on to demonstrate that the synergistic rescue of ∆F508-CFTR with a combination of compounds targeting both structural deficiencies (Nat Chem Biol, 2013; 9:444-54). In addition, he demonstrated elimination of unfolded CFTR from the cell surface, as part of a peripheral protein quality control system (Science, 2010; 329:805-810), which was then shown, in collaboration with Dr. Shrier, to also apply to the hERG potassium channel (Mol Biol Cell 2013; 24:3787-3804). Recent studies from Dr. Lukacs revealed that the VX-770 potentiating gating compound under clinical investigation destabilizes the channel and target the CFTR channel for degradation (Sci Transl Med 2014; 6(246): 246ra97).
Roles of NHEs in neuronal disease: Drs. McKinney and Orlowski have begun a fruitful collaboration with a recent paper demonstrating that NHE6 and NHE9 may play a previously unrecognized, role in membrane transport and receptor trafficking at glutamatergic synapses that are important for learning and memory (J. Neurosc. 2013; 33:1098-1916). They also have recently shown that impaired posttranslational processing and trafficking of an endosomal Na+/H+ exchanger NHE6 mutant is associated with X-linked intellectual disability and autism (Neurochem Int 2013; S0197-0186(13):00248-9).
Molecular mechanisms of Alzheimer’s disease: Drs. Munter and Multhaup identified Cys466 as a key residue for metal ion chelation and to be the core of an oligomerization motif of the BACE1-TMS peptide (J Am Chem Soc 2013; 135:19354–19361). Dr. Multhaup also identified the first familial mutation in the amyloid precursor protein (APP) located at the alpha secretase cleavage site and describe a unique phenotype of the mutant Ab42 protein that is considered the likely cause of the early onset dementia observed in that patient (EMBO Mol Med 2012; 4:647-59). In addition, he has shown that the nuclear translocation of Aβ42 impacts gene regulation and alters the expression profiles of AD-associated genes (J Biol Chem 2014; 289:20182-20191).
Neuronal basis for pain hypersensitivity: Dr. Sharif has shown that transplantation of immature GABAergic neurons into the adult mouse spinal cord reverses the pain symptoms produced by peripheral nerve injury. This suggests that these GABAergic neurons overcome the spinal cord hyperexcitability that is a hallmark of nerve injury-induced neuropathic pain (Neuron 2012; 74: 663-75). More recent work under revision for Neuron demonstrates that the loss of function of a subset of glycinergic spinal cord neurons is responsible for the loss of inhibition that underlies mechanical hypersensitivity.
Origin of complex dynamics and reentrant rhythms: Dr. Shrier, in collaboration with Dr. Leon Glass, has shown that a blocker of the hERG potassium channel leads to drug-induced bifurcations and chaotic dynamics in cardiac tissue culture (Phys Rev Lett 2009; 103(5):058101, 1-4). A second study, shows that spiral wave chirality is determined by the precise location of a region of conduction block and pacing frequency (Phys Rev Lett 2014; 113(15):158101, 1-5).