A characteristic feature of voltage-gated Na+ (Nav) channels is their voltage-dependent activation and inactivation. The range of membrane potentials in which a channel undergoes activation and inactivation can dramatically effect cell excitability and important cellular processes such as secretion. Nav channels in pancreatic β-cells undergo inactivation at very negative membrane potentials, rendering most Nav channels inactive and thus unable to contribute to the electrical activity of the cell (Plant, 1988). β-cells express Nav1.3, Nav1.6 and Nav1.7. We hypothesised that these channels have different properties in β-cells compared to other cell types. The aim of the project was to characterise these channels in a β- and non-β-cell model and to identify potential modulators of Nav channel properties in β-cells. The channels were transfected into a rat insulinoma cell line (INS1-832) and a human embryonic kidney (HEK) cell line to model a β- and non-β-cell environment, respectively. Using whole cell patch clamp the activation and inactivation properties of the Nav channel were measured. Statistical significance was calculated using unpaired Student’s t test. Half-maximal inactivation (V0.5) of Nav1.7, Nav1.6 and Nav1.3 expressed in HEK cells was observed at -68 + 2 mV (n=8), -51 + 3 mV (n=5) and -48 + 2 mV (n=5), respectively. However when expressed in INS1-832 cells the V0.5 of Nav1.7, Nav1.6 and Nav1.3 displayed a significant hyperpolarising shift to -93 + 2 mV (p<0.001, n=8), -76 + 1 mV (p <0.001, n=17) and -86 + 2 mV (p<0.01, n=13), respectively. This effect could also be observed in Nav channels that are not usually expressed in β-cells. For example the cardiac α-subunit Nav1.5 also produced a significant hyperpolarising shift in V0.5 from -106 + 2 mV (n=9) to -77 + 2 mV (p<0.001, n =5), when expressed in INS1-832 and HEK cells, respectively. The shift in V0.5 of all the channels occurred without a significant change in the activation properties of the channel. Receptor tyrosine kinases (RTKs) have been previously reported to modulate Nav channel current densities (Fanger et al. 1995). The insulin receptor is a RTK and it was hypothesised that insulin secreted from β-cells may act via autocrine signalling to modulate Nav channel inactivation. However application of an insulin receptor antagonist had no effect. Furthermore modulation of downstream insulin receptor signalling molecules such as PIP2, which is known to alter the gating properties of the ATP-sensitive potassium channel, also did not affect Nav channel modulation. The results suggest a β-cell-specific modulation of Nav inactivation properties. Identification of this cell specific modulator warrants further investigation as it alters the inactivation property of a broad spectrum of Nav channels and from a β-cell perspective recruitment of the channels could provide a novel mechanism for increasing insulin secretion.