Major research aims
Within every phylum of the animal kingdom, voltage-gated sodium (NaV) channels are nature’s answer to the need for fast intra-organism communication and coordination. Utilizing the Na+ gradient across the cell membrane, they generate electrical signals that telegraph messages to and from a central hub. Not surprisingly, Nav channels support many critical physiological processes such as sensory perception, heart and brain function, and muscle movement, and are targeted by drugs as well as animal venoms. These fascinating molecules have been at the core of our research for 20 years. We believe that we are now at the point where we can exploit the genetic, structural, and functional knowledge that we and others have gathered about Nav channels to develop solutions to human problems.
Nav channels play a vital role in the perception of pain, since they rapidly transduce afferent stimuli in the skin to the spinal cord and the brain (DOI: 10.1038/nature17976). Although several Nav channel subtypes have been associated with severe pain disorders, the Nav1.9 subtype is by far the most elusive. The MPNG lab investigates the peculiar electrophysiological properties of Nav1.9 in heterologous expression systems as well as isolated dorsal root ganglionic neurons. Furthermore, we aim to elucidate the molecular players that influence Nav1.9 expression and gating, and relate this to in vivo pain experience using genetically-modified mouse lines and behavioral assays. We strive to gain insights in pain signaling on a molecular and integrative level and lay the foundation for future drug development efforts.
Even though the scientific community is in virtual agreement on a prominent contribution of Nav1.9 (gene name: SCN11A) to pain, the role of this Nav channel subtype in itch is virtually unknown. Yet, patients with a Nav1.9 p.L811P mutation consistently report debilitating chronic itch. Our previous work uncovered a role for Nav1.9 in transmitting acute itch signals via peripheral nerves, likely via a subset of prurinergic fibers (DOI: 10.1172/JCI122481). We are now investigating this channel in relation to chronic itch, the dominant clinical phenotype as well as other symptoms that plague patients with Nav1.9 mutations. To this end, we developed a set of genetically modified mouse strains and are in the process of determining a pharmacological profile of Nav1.9.
Our lab investigates β-subunit mutations found in juvenile patients with Generalized Epilepsy with Febrile Seizures (GEFS+) and Early Infantile Epileptic Encephalopathy (EIEE). The functional consequences of these mutations are typically linked to aberrant function of Nav1.1, Nav1.2 and Nav1.6, the three most abundantly expressed Nav channels in the human brain. The MPNG lab also explores mutations in ligand-gated GABAa receptors which are linked to West syndrome (WS), a severe form of infantile epilepsy diagnosed in 1 in 3500 children. To investigate whether GABAa receptor mutations seen in WS patients dampen inhibitory transmission, we perform electrophysiological recordings on Xenopus oocytes (TEVC), HEK293 T cells, hippocampal neurons and brain slices. This work has the potential to contribute new conceptual insights into the role of GABAa receptors in infantile spasms and can directly affect patient lives.
Similar to their role in mammals, Nav channels are also essential for invertebrates. We have had a long-standing interest in insect physiology and in using arachnid toxins to interrogate membrane protein function. Our focus on insect Nav channels was further heightened by reports from media outlets (2016) of widespread honeybee death in Florida as a result of insecticide spraying against Zika virus-infected mosquitos. Two years before this event, we identified Dc1a, a toxin from the American desert bush spider Diguetia canities that acts on insect Nav channels but is non-toxic to mammals. Interestingly, Dc1a exploits a particular locus in the insect channel to incapacitate the German cockroach but not the closely related American cockroach (DOI: 10.1038/ncomms5350). This proof-of-principle data bodes well for the design of species-selective pesticides. Propelled by the urgent need for a solution to the global pesticide problem, we would now build on our expertise in identifying species-specific toxins to provide a framework for designing natural pesticides.