Voltage-activated sodium (Nav) channels form the cornerstones of fast electrical signaling in the human body. On a molecular level, Nav channels consist of four similar domains that each contains a voltage sensor which largely resides within the lipid membrane. These sensors can interact with ?1 and ?4, two associated glycoproteins that regulate the gating properties of the channel and modulate channel expression levels. Although a link between Nav channel mutations and particular diseases has been established, little is known about the regulatory influence of ?1 and ?4 on Nav channels and how mutations within these two molecules relate to epilepsy (?1) and cardiac (?4) syndromes. To begin to understand this causal relationship, we need to establish an interaction model that reflects the mechanism by which ?1 and ?4 regulate the functional properties of the channel. We propose that these ?-subunits tune the response of Nav channels to membrane potential changes by influencing voltage-sensing domains. To help examine this notion, we will assess the impact of an epilepsy-related ?- subunit mutation on its ability to alter correct signaling complex assembly or modify channel gating. To achieve our goals, we will use Nav1.2 as a model channel since this particular isoform can interact with ?1 and ?4 and is a risk gene for epilepsy. Although ?-subunit crystal structures provide atomic resolution information, a relative orientation in respect to the Nav channel is required to understand their interaction. Identification of anchoring residues in both partners will help orient functional regions within the extracellular and transmembrane domains, thereby providing the experimental basis for docking ?1 and ?4 onto the Nav channel. The resulting model will offer a starting point to explain mutational effects, which is necessary to accurately interpret and correct pathogenic behavior.
Our goal is to elucidate the mechanisms underlying the complex effects of auxiliary subunits on voltage-gated sodium (Nav) channels function and pharmacology. As such, we will help define the function of the Nav channel signaling complex in humans under normal and pathological conditions, which is essential to our understanding of how we can target it with drugs.
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