Kelvin Chan

Kelvin ChanImage: Kelvin Chan

Education:

B.S. University of Virginia (2013)

Current Position:

6th Year MSTP

3rd Year Medical Student

Advisor:

Lonnie Wollmuth, PhD

Graduate Program:

Program in Neuroscience

Research Interest:

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease where patients may develop perturbations in neurological and psychiatric function. A subset of these patients produce anti-dsDNA antibodies that cross-react with the NMDA receptor (DNRAbs). NMDA receptors are glutamate-gated ion channels that are essential for excitatory signaling in the nervous system. They are obligate heterotetramers, typically composed of two GluN1 subunits and two GluN2 subunits. DNRAbs mediate synaptic dysfunction, cognitive impairment, and excitotoxicity through NMDA receptor activity, largely in the hippocampus. The two major GluN2 subunits in the hippocampus are GluN2A and GluN2B and DNRAbs bind to both GluN2A and GluN2B-containing NMDA receptors. Nevertheless, the specific effect of DNRAbs on NMDA receptors and which NMDA receptor subunits are targeted remain elusive. A major function of synaptic NMDA receptors is to convert synaptically released glutamate into an electrical signal by opening of its associated ion channel, a property called ion channel gating. We show that DNRAbs exert subunit-specific effects on NMDA receptor gating. At a moderate concentration (patient titers), DNRAbs increase peak amplitude of glutamate-induced currents only in GluN2A-containing receptors but not GluN2B-containing receptors. Using high-resolution single channel recordings, we show that DNRAbs increase the mean open probability (Po) of GluN2A-containing receptors, but not in those containing GluN2B, suggesting that DNRAbs stabilize GluN2A-containing receptors in the open state. In the hippocampus, NMDA receptors are typically tri-heteromeric, containing both GluN2A and GluN2B subunits.  We find that DNRAbs potentiate GluN2A/GluN2B tri-heteromeric receptors, suggesting that GluN2A confers dominance of antibody susceptibility to NMDA receptors. Using transgenic mice to ablate GluN2A and immunogenized to produced DNRAbs, we find that GluN2A is essential for both acute and chronic phases of SLE pathology in the dorsal CA1 region of the hippocampus. Taken together, these findings suggest that targeted therapies for NPSLE patients to improve neurocognitive function should be directed towards GluN2A.

Publications:

Zoodsma J*, Chan K*, Golann D, Bhandiwad A, Napoli A, Liu G, Syed S, Burgess H, Sirotkin H†, Wollmuth LP†. A model to study NMDA receptors in early nervous system development. J. Neurosci. pre-print, pii: JN-RM-3025-192020. [DOI: 10.1523/JNEUROSCI.3025-19.2020]

 

Chan K*, Nestor J*, Huerta TS, Certain N, Moody G, Kowal C, Huerta PT, Volpe BT, Diamond B†, Wollmuth LP†. Lupus autoantibodies act as positive allosteric modulators at GluN2A NMDA receptors and impair spatial memory. Nat. Commun. 11, 1403, 2020. [DOI: 10.1038/s41467-020-15224-w]

 

Esmenjaud JB*, Stroebel D*, Chan K, Grand T, David M, Wollmuth LP, Taly A, and Paoletti P†. An inter-dimer allosteric switch controls NMDA receptor activity. EMBO J. 38(2), 2019. [DOI: 10.15252/embj.201899894.]

 

Amin J*, Salussolia C*, Chan K, Regan M, Dai J, Zhou HX, Furukawa H, Bowen M, and Wollmuth LP†. Divergent roles of a peripheral transmembrane segment in AMPA and NMDA receptors. J. Gen Physiol. 149(6):661-680, 2017. [DOI: 10.1085/jgp.201711762]

 

Breuss MW, Fritz T, Gstrein T, Chan K, Ushakova L, Yu N, Vonberg FJ, Werner B, Elling U, Keays DA†. Mutations in the murine homologue of TUBB5 cause microcephaly by perturbing cell cycle progression and inducing p53-associated apoptosis. Development 143(7):1126-33, 2016. [DOI: 10.1242/dev.131516]

 

Breuss MW*, Morandell J*, Nimpf S, Gstrein T, Lauwers M, Hochstoeger T, Braun A, Chan K, Sánchez Guajardo ER, Zhang L, Suplata M, Heinze KG, Elsayad K, Keays DA†. The expression of Tubb2b undergoes a developmental transition in murine cortical neurons. J. Comp. Neurol. 523:2161 – 2186, 2015.  [DOI: 10.1002/cne.23836]

 

Kodis E, Smindek R, Kefauver J, Heffner D, Aschenbach K, Brennan E, Chan K, Lambeth P, Lawler J, Sikora A, Gamage KT, Vercroysse N, Deppmann CD†. First Messengers. eLS, 2012. [DOI: 10.1002/9780470015902.a0024167]


*Equal Contributor

†Senior Author