Stanford Advisors


All Publications


  • Precise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin. Nature communications Elleman, A. V., Devienne, G., Makinson, C. D., Haynes, A. L., Huguenard, J. R., Du Bois, J. 2021; 12 (1): 4171

    Abstract

    Here we report the pharmacologic blockade of voltage-gated sodium ion channels (NaVs) by a synthetic saxitoxin derivative affixed to a photocleavable protecting group. We demonstrate that a functionalized saxitoxin (STX-eac) enables exquisite spatiotemporal control of NaVs to interrupt action potentials in dissociated neurons and nerve fiber bundles. The photo-uncaged inhibitor (STX-ea) is a nanomolar potent, reversible binder of NaVs. We use STX-eac to reveal differential susceptibility of myelinated and unmyelinated axons in the corpus callosum to NaV-dependent alterations in action potential propagation, with unmyelinated axons preferentially showing reduced action potential fidelity under conditions of partial NaV block. These results validate STX-eac as a high precision tool for robust photocontrol of neuronal excitability and action potential generation.

    View details for DOI 10.1038/s41467-021-24392-2

    View details for PubMedID 34234116

  • Molecular mechanism of activation-triggered subunit exchange in Ca2+/ calmodulin-dependent protein kinase II ELIFE Bhattacharyya, M., Stratton, M. M., Going, C. C., McSpadden, E. D., Huang, Y., Susa, A. C., Elleman, A., Cao, Y. M., Pappireddi, N., Burkhardt, P., Gee, C. L., Barros, T., Schulman, H., Williams, E. R., Kurivan, J. 2016; 5

    Abstract

    Activation triggers the exchange of subunits in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones.

    View details for DOI 10.7554/eLife.13045

    View details for Web of Science ID 000376257400001

    View details for PubMedID 26949248

    View details for PubMedCentralID PMC4859805