Voltage-gated sodium channels (VGSCs) are essential for action potential generation. Regulation of voltage- gated ion channel function is an important pathway by which neuronal signaling and brain function is regulated, and G-protein coupled receptors (GPCRs) form a major element of the endogenous transduction mechanisms by which this occurs. However, unlike other ion channels, VGSCs have been believed to be relatively insensitive to modulation by GPCR signaling. We have recently identified a pathway that is modulated by agents known to interact with the GPCR CB1 (cannabinoid receptor). This pathway is widespread, present in the vast majority of neocortical neurons, and strong enough to completely and reversibly block VGSC currents when maximally stimulated. This novel, dynamic signaling pathway is positioned to substantially modulate neuronal excitability and brain function. Detailed knowledge about the underlying mechanisms is crucial to understand its many effects. These preliminary findings may fundamentally change our understanding of the mechanism of action of endocannabinoids. The objectives of this proposal are to determine how endocannabinoids regulate VGSCs. We will complete this undertaking by studying VGSC function using patch- clamp methods and live cell imaging in neurons in acute neocortical brain slices, following acute isolation, and in primary cultures. We will employ mouse models. We are ideally suited to perform this project because of our preliminary data and expertise. Successful completion of these specific aims will characterize the mechanism of action of inhibition of sodium channels by this novel pathway and characterize a new mechanism by which endocannabinoids can affect neuroplasticity. Our rationale is that the identification and characterization of a novel and prevalent receptor(s) and downstream pathway will facilitate our understanding of a prevalent and potentially powerful neurobiological signaling pathway. Elucidation of the pathway will provide a detailed characterization of a new drug target that may be relevant to a wide range of diseases characterized by unbalanced excitability.

Public Health Relevance

Voltage-gated sodium channels are key proteins that generate and transmit electrical signals within neurons and muscle cells. Altered function of these channels causes a wide range of diseases that are important to Veterans, including epilepsy, peripheral neuropathy, cardiac arrhythmias, and paralysis. Moreover, drugs that target voltage-gated sodium channels are used to treat epilepsy, acute pain, and cardiac arrhythmias. We have discovered a new pathway that regulates the activity of voltage-gated sodium channels and is sensitive to endogenous cannabinoids. In this proposal, we will characterize this signaling pathway that may constitute a new drug target. Once we have identified the components of the pathway it may be possible for new drugs to be identified to improve treatment of important diseases experienced by Veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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Portland VA Medical Center
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Mattheisen, Glynis B; Tsintsadze, Timur; Smith, Stephen M (2018) Strong G-Protein-Mediated Inhibition of Sodium Channels. Cell Rep 23:2770-2781
Williams, Courtney L; Smith, Stephen M (2018) Calcium dependence of spontaneous neurotransmitter release. J Neurosci Res 96:335-347
Tsintsadze, Timur; Williams, Courtney L; Weingarten, Dennis J et al. (2017) Distinct Actions of Voltage-Activated Ca2+ Channel Block on Spontaneous Release at Excitatory and Inhibitory Central Synapses. J Neurosci 37:4301-4310
Jones, Brian L; Smith, Stephen M (2016) Calcium-Sensing Receptor: A Key Target for Extracellular Calcium Signaling in Neurons. Front Physiol 7:116