Influence of Voltage Gated Sodium Channels on Cellular Motility and Inflammation

Recent studies demonstrate that voltage--gated sodium (Nav) channels have physiological and developmental roles beyond the generation and propagation of action potentials. For example, we have found that the electroretinogram of young mice missing the Nav1.6 isoform displays profound abnormalities that cannot be explained in the context of its canonical role. In addition, various Nav channel isoforms have been found in non-excitable cells such as glia, immune cells, and neoplastic cells where they appear to regulate aspects of trafficking, endocytosis, differentiation and motility. The overarching theme of my program revolves around the discovery of new roles for VGSCs and determining the mechanism by which they exert their influence, as well as the development of new tool to address related questions. We know that extensive remodeling occurs after eye opening and is dependent on visual experience. Photoreceptors mature quickly in the days following the first visual experiences but this aspect of retinal development has received relatively little attention. We have discovered that Nav channels indirectly regulate how sensitive photoreceptors are to light during a period that follows the first visual experiences. Diffusible molecules, called neurotrophins, are released from neurons of the inner retina and glial cells to regulate photoreceptor function. We believe that Nav channels contribute to the transport and release of neurotrophins and I propose to study these processes in detail in the optic nerve. We have recently discovered that mice with low levels of the channel Nav1.6 produce reduced levels of the pro-inflammatory cytokine IL-6 in two models of inflammation (neuro-inflammation and systemic inflammation), with decreased release of activated neutrophils - the first line of defense of the immune system - in response to a stimulus which mimics a bacterial infection. I therefore propose to study in detail how Nav1.6 and other Nav channels regulate neutrophil function. Finally, the function of individual Nav channel types, among the ten that are known, has been difficult to assess because the drugs used to study them discriminate poorly. We have recently used a novel approach to block the function of individual types of Nav channels with high precision by using antibodies. We propose to further characterize these antibodies to help us address the above objectives and to provide the ion channel research community new tools to investigate sodium channels. These fundamental discoveries will establish foundations upon which innovations that benefit Canadians can be developed. For example, understanding how neurotophin transport and release is modulated by Nav channels has implications for our understanding of retinal degenerations. Finally, this program will enable the training of the next generation of Canadian neuroscientists in a rich multidisciplinary environment.