Mechanisms of voltage-gated sodium channel inhibition by phrixotoxin
- Research Opportunity
- PhD, Honours
- Number of Honour Places Available
- Medicine and Radiology
- Florey Institute of Neuroscience & Mental Health
Voltage-gated Nav1.2 sodium channel mutations are associated with a number of neurological disorders, including epilepsy. Clinically used drugs and experimental compounds can target Nav1.2 channels and modulate neuronal excitability. Among these, phrixotoxin-3 from the venom of the tarantula Grammostola rosea efficiently blocks Nav1.2 channel current, presumably by altering Nav1.2 channel gating. Phrixotoxin-3 is a valuable research tool, capable of potently and selectively inhibiting Nav1.2 channels with a half-maximum inhibitory concentration of 0.6 nM, which represents a 100-fold selectivity for Nav1.2 over other neuronal voltage-gated sodium channels. The precise mechanism of action of phrixotoxin-3 on various sodium channels is unknown.
The goal of this project is to elucidate the effect of phrixotoxin-3 on a series of neuronal human sodium channels. We will study Nav1.1, Nav1.2, Nav1.3 and Nav1.6 channels constitutively expressed in mammalian cell lines using conventional voltage-clamp and/or dynamic clamp techniques. In voltage clamp, the biophysical properties of sodium channels such as voltage-dependence of activation and inactivation, recovery from inactivation, and use-dependence will be determined in the absence and presence of PTx3, respectively. In dynamic clamp, sodium current recorded in mammalian cells will be incorporated into a biophysically realistic model of the distal axon initial segment compartment of a cortical pyramidal neuron. The resulting hybrid neuron model can directly predict the impact of sodium channel inhibition/modulation on neuronal excitability (see details of this approach in Berecki et al. Proc Natl Acad Sci U S A. 2018.115:E5516-E5525). Dynamic clamp represents a significant advance over conventional electrophysiological and computational modelling approaches and is well positioned to impact drug discovery in genetic epilepsy and is particularly relevant in the current era of precision medicine.
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Research NodeFlorey Institute of Neuroscience & Mental Health
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