Ion channels and neurotransmitter receptors are complex and dynamic proteins that play central roles in neural and synaptic signaling, and their dysfunction is associated with an array of human diseases. In the Senatore lab, we seek to gain a broad, phylogenetic understanding of how these important genes evolved, including their intrinsic structure-function properties, their interactions with accessory subunits and other proteins, the mechanisms for their cellular localization, and ultimately, their physiological functions.
Research Areas
Currently, we are focusing on the following ion channels and neurotransmitter receptor types:
-Voltage-gated Ca2+ channels, responsible for neurotransmitter release and muscle contraction.
-Neuropeptide and proton-gated Na+ channels (i.e. DEG/ENaC channels), involved in pain signaling, learning and memory, and synaptic transmission.
-Ionotropic glutamate receptor homologues of the NMDA, AMPA and Kainite receptors, major players in excitatory synaptic transmission in the mammalian brain.
-The sodium leak channel NALCN, involved in circadian rhythm, neural excitability, and sensitivity to anesthetics.
Trichoplax adhaerens
Our main research subject is the fascinating animal Trichoplax adhaerens, which diverged from other animals roughly 600 million years ago, lacks neurons and synapses, and yet bears most gene homologues required for neural/synaptic signaling. Interestingly, despite lacking a nervous system, we and others have shown that Trichoplax can coordinate its various cell types for directed locomotive behavior including social feeding, chemotaxis, and phototaxis. Trichoplax is at a strategic phylogenetic position for understanding the evolution of animal complexity, including cell types, development, and cellular/neural signaling.
Because ion channel and neurotransmitter receptor function depends on sub-cellular localization, a focus in the lab is the evolution of protein-protein interactions that govern trafficking and localization of ion channels and neurotransmitter receptors to discrete cellular compartments. This is particularly important for voltage-gated calcium channels, where their differential localization across the synapse defines their functions for pre-synaptic exocytosis, and post-synaptic contraction in muscle, and control of gene expression in neurons.
Techniques and Approach
Personnel in the lab learn to integrate a broad range of techniques including light and fluorescence microscopy, molecular biology, electrophysiology, pharmacology, cell culture, protein biochemistry, behavioral analysis, genomics/transcriptomics, and bioinformatics.
