OVERVIEW

We have a broad interest in the evolution of physiological processes at the molecular, cellular and organismal levels. We use molecular evolution to identify and characterize key features molecules and cells that allow them to perform their physiological roles. In a practical sense, this knowledge can be used to manipulate the physiology of organisms to do things like adapt crops to climate change or treat human diseases. But the evolutionary history of life is the greatest story of all time, and it is also a privilege to get to tell some cool parts of it.

The parts we are most interested in telling are the evolutionary history of electrical signaling and the ion channels that underlie it. Electrical signaling is the basis of fast communication in the nervous system and we are interested in how ion channels and the structures of neurons evolved to enable it. We are also interested in questions like how plant ion channels evolved to close and open stomata to control photosynthesis or why the ion channel sets of ancient single celled eukaryotes are often far more complex than their multicellular relatives.

CURRENT PROJECTS

The functional and molecular evolution of K⁺ channels in animals. We have long beennterested in figuring out when and how the functionally diverse ion channels that underlie complex electrical signaling in our nervous systems evolved. The functional protein domains our channels are made from are ancient and most can be traced back to origins in prokaryotes. Similarly, most major structural classes (specific combinations of protein domains) canv be traced to prokaryotes or ancestral eukaryotes. But the functionally unique gene families that underlie neuronal signaling are typically animal specific. We are looking at the functional and molecular diversity of these channels, and voltage-gated K⁺ channels in particular, in early-diverging animal lineages such as comb jellies and cnidarians to figure out when our ion channels gained their characteristic functional features, to gain new insights into the structural requirements for these functions and to understand what evolutionary pressures might have driven their origins. One of the most interesting insights is that these early animals, despite lacking centralized nervous systems, often have a higher diversity of ion channels than we do. We would love to figure out why!

The evolution of subunit assembly in ion channels. Neurons used dozens of ion channels to orchestrate complex electrical signaling – from the initiation of signals at sensory ending and synapses to tuning of excitability, conduction of electrical signals and generation of diverse firing patterns. Add on top of that most ion channels are multimeric. This creates a very complex problem – how do you get the ion channel subunits to assemble with the correct partners, and only the correct partners, in the correct stoichiometries to form the exact ion channels the neuron needs? If this isn’t done correctly, channels won’t have the right properties and won’t get to the right places in the cell, and electrical signaling will be disrupted. We know a lot about which subunits can and can’t co-assemble and how many subunits make a functional channel, but a lot less about what stoichiometries are assembled in vivo and very little about why subunits assemble only with specific partners in specific stoichiometries.

 

 

Principles of Ion Channel Assembly. We are trying to figure out the principles of ion channel subunit assembly using an evolutionary approach and voltage-gated K⁺ channels as a model system. These channels are tetrameric (made of four subunits) and neurons require multiple functionally independent types to signal properly. We have multiple gene subfamilies that encode these different types of channels, and they remain functionally independent because subunits cannot co-assemble across subfamily boundaries. Furthermore, some subunits are self-compatible and can form homotetramers (channels made of four identical subunits) while others are self-incompatible and must assemble as heteromers (channels made of homologous but not identical subunits). We have identified multiple instances for the evolution of these channel assembly phenotypes in animals ranging from comb jellies and see anemones all the way up to mammals and are working to identify how subunit assembly evolves on a molecular level. What are the mutations that generate new assembly-exclusive subfamilies? What mutations affect self-compatibility? What are the molecular mechanisms that determine how many of each type of subunit gets into a heteromer? Understanding these principles will help us determine which channels form in vivo and what their functional properties are.

Evolution of gating phenotypes in ion channels. Ion channels are typically gated pores – they all contribute to electrical signaling because they provide a pathway for some type of ion to cross the impermeable plasma membrane, but the conditions under which they contribute are determined by the stimuli that gate (open or close) the pore. We are interested in the evolution of ion channel gating for two major reasons: 1) Learning how and when various key gating features arose can give us new structural insights into gating mechanisms and the evolution of electrical signaling, and 2) understanding how various ion channels will shape the physiology of organisms. We are combining phylogenetic and ancestor analyses with functional characterization and structural modeling to better understand how voltage- and ligand- gating have evolved in the Cyclic Nucleotide Binding Domain channel superfamily across the eukaryotic tree of life. These channels are gated by the interactions of a voltage sensor domain in the membrane and a cytoplasmic CNBD, but the voltage stimuli and ligands that operate them have changed many times during the course of evolution. We want to use these instances of evolutionary change to characterize the structural mechanisms that underlie voltage-gating phenotype and ligand specificity. We are particularly interested in the CNBD superfamily of channels in ciliate protozoans, algae and land plants where the superfamily has expanded and diversified at the molecular level to a surprising extent. The ciliate Paramecium tetraurelia has more than 250 sequence diverse CNBD superfamily channel genes (> 10 times the number in mammals!) and promises to be a rich ground for identifying new principles of gating in this channel superfamily. Furthermore, plant CNBD superfamily channels play key roles in the regulation of photosynthesis, but why they have certain voltage-gating phenotypes is not understood and the native ligands that potentially modulate them have not been identified. The answers may lie in a burst of CNBD superfamily diversification in the green algae!

 

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