Research
In electrically-excitable cells, the voltage-gated sodium (Nav) channel initiates the action potential. Sodium channels are major pharmacological targets and are implicated in pathologies such as heart disease, epilepsy, and chronic pain. The sodium channel consists of a ~260 kDa alpha-subunit with associated 35-40 kDa beta-subunits. The beta-subunits modulate the electrophysiological behaviour of the channel and help transport the channel to the plasma membrane.
There are ten alpha-subunit and four beta-subunit genes, expressed in distinct tissue-specific patterns. All Nav beta-subunits possess a single extracellular immunoglobulin (Ig) domain, connected via a stalk to an alpha-helical transmembrane domain and an intracellular carboxy-terminal region.
We study the role played by the beta 3-subunit in Nav channel structure and function. In mice, deletion of the beta 3-subunit gene (Scn3b) is associated with cardiac arrhythmias. To provide a better understanding of the beta 3-subunit, we have investigated its structure using X-ray crystallography. We have shown that the beta3-subunits can trimerise via their Ig domains, and induce the formation of Nav channel alpha-subunit oligomers, including trimers.
These results provide a new interpretation of previous electrophysiological data, and raise a new set of questions. Does the cross-linking of Nav channels by beta 3 lead to functionally coupled channels? Can different Nav alpha-subunits be cross-linked together? Do the beta-subunits help stabilise the Nav channel into larger-scale protein clusters on the plasma membrane?
Publications
SILAC-iPAC: a quantitative method for distinguishing genuine from non-specific components of protein complexes by parallel affinity capture. Rees JS, Lilley KS, Jackson AP. J Proteomics. 2015 Feb 6;115:143-56.
A new look at sodium channel β subunits. Namadurai S, Yereddi NR, Cusdin FS, Huang CL, Chirgadze DY, Jackson AP. Open Biol. 2015 Jan;5(1):140192.
SDF-1 chemokine signalling modulates the apoptotic responses to iron deprivation of clathrin-depleted DT40 cells. Pance A, Morrissey-Wettey FR, Craig H, Downing A, Talbot R, Jackson AP. PLoS One. 2014 Aug 27;9(8):e106278.
New insights into the DT40 B cell receptor cluster using a proteomic proximity labeling assay. Li XW, Rees JS, Xue P, Zhang H, Hamaia SW, Sanderson B, Funk PE, Farndale RW, Lilley KS, Perrett S, Jackson AP. J Biol Chem. 2014 May 23;289(21):14434-47.
Crystal structure and molecular imaging of the Nav channel β3 subunit indicates a trimeric assembly. Namadurai S, Balasuriya D, Rajappa R, Wiemhöfer M, Stott K, Klingauf J, Edwardson JM, Chirgadze DY, Jackson AP. J Biol Chem. 2014 Apr 11;289(15):10797-811.
The immunoglobulin domain of the sodium channel β3 subunit contains a surface-localized disulfide bond that is required for homophilic binding. Yereddi NR, Cusdin FS, Namadurai S, Packman LC, Monie TP, Slavny P, Clare JJ, Powell AJ, Jackson AP. FASEB J. 2013 Feb;27(2):568-80.
