Role of dimer formation in modulating neuronal sodium channel properties

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Summary/Abstract Voltage-gated sodium channels are major contributors to the generation and propagation of action potentials in neurons and muscle. Changes in the properties of sodium currents can substantially alter the excitability of excitable cells. Indeed, sodium channel variants have been associated with a wide array of disorders of excitability, including pain, epilepsy, ataxias, autism, myotonias and arrythmias. A multitude of sodium channel disease mutations have been characterized. Many mutations can alter diverse sodium current properties and the observed changes can range from profound to subtle. Interestingly, although many mutations have dominant effects, the vast majority of characterizations have focused on isolated channel variants. Several recent studies suggest that some voltage-gated sodium channels can form dimers and that dimer formation may alter the impact of specific variants on sodium current properties. If dimer formation substantially alters sodium current properties and/or the physiological consequences of disease mutations, then investigations of the functional consequences of disease mutants in the presence of wild-type channels, other variants and even other isoforms may be needed to fully understand how specific channel isoforms and variants contribute to electrogenesis and different pathological conditions. We will investigate if dimer formation can result in changes in multiple properties, including activation, deactivation, fast inactivation, slow inactivation and persistent currents of Nav1.1 and Nav1.7 isoforms. Next, we will use Proximity Ligation Assays to examine the potential of dimer formation on brain isoforms in cell systems. Finally, we will examine potential consequences of dimer formation on Nav1.6 and Nav1.7 channel variants associated with pain expressed in dorsal root ganglion neurons to help determine if dimers can impact the properties of channels in a natural cell background. This exploratory research project targets several key gaps in our knowledge relating to the potential consequences of VGSC dimers. A fuller understanding of this phenomena could lead to a more complete understanding of channelopathies and possibly spur the development of novel treatment strategies.