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.
|Gilchrist, John; Bosmans, Frank (2018) Using voltage-sensor toxins and their molecular targets to investigate NaV 1.8 gating. J Physiol 596:1863-1872|
|Männikkö, Roope; Shenkarev, Zakhar O; Thor, Michael G et al. (2018) Spider toxin inhibits gating pore currents underlying periodic paralysis. Proc Natl Acad Sci U S A 115:4495-4500|
|Osteen, Jeremiah D; Sampson, Kevin; Iyer, Vivek et al. (2017) Pharmacology of the Nav1.1 domain IV voltage sensor reveals coupling between inactivation gating processes. Proc Natl Acad Sci U S A 114:6836-6841|
|Wingerd, Joshua S; Mozar, Christine A; Ussing, Christine A et al. (2017) The tarantula toxin ?/?-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity. Sci Rep 7:974|
|Kwon, Soohyun; Bosmans, Frank; Kaas, Quentin et al. (2016) Efficient enzymatic cyclization of an inhibitory cystine knot-containing peptide. Biotechnol Bioeng 113:2202-12|
|Ahern, Christopher A; Payandeh, Jian; Bosmans, Frank et al. (2016) The hitchhiker's guide to the voltage-gated sodium channel galaxy. J Gen Physiol 147:1-24|
|Salvatierra, Juan; Bosmans, Frank (2016) A painful tale about synthetic scorpion toxins. Channels (Austin) 10:256-7|
|Das, Samir; Gilchrist, John; Bosmans, Frank et al. (2016) Binary architecture of the Nav1.2-?2 signaling complex. Elife 5:|
|Osteen, Jeremiah D; Herzig, Volker; Gilchrist, John et al. (2016) Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature 534:494-9|