Abstract
Neuronal resting potential can tune the excitability of neural networks, affecting downstream behavior. Sodium leak channels (NALCN) play a key role in rhythmic behaviors by helping set, or subtly changing neuronal resting potential. The full complexity of these newly described channels is just beginning to be appreciated, however. NALCN channels can associate with numerous subunits in different tissues and can be activated by several different peptides and second messengers. We recently showed that NALCN channels are closely related to fungal calcium channels, which they functionally resemble. Here, we use this relationship to predict a family of NALCN-associated proteins in animals on the basis of homology with the yeast protein Mid1, the subunit of the yeast calcium channel. These proteins all share a cysteine-rich region that is necessary for Mid1 function in yeast. We validate this predicted association by showing that the Mid1 homolog in Drosophila, encoded by the CG33988 gene, is coordinately expressed with NALCN, and that knockdown of either protein creates identical phenotypes in several behaviors associated with NALCN function. The relationship between Mid1 and leak channels has therefore persisted over a billion years of evolution, despite drastic changes to both proteins and the organisms in which they exist.
Highlights
Ion channels are the workhorses of neuronal excitability
Our results suggest an ancient association between a cysteinerich motif we call the Mid1 domain and leak channels
This association, which predates the divergence of the animal and fungal lineages, has been preserved in fungal calcium channels and animal NALCN despite structural and functional changes over deep evolutionary time
Summary
Ion channels are the workhorses of neuronal excitability. By controlling the passage of ions across the cell membrane of neurons, ion channels produce and propagate action potentials that transmit information throughout the brain. A gene encoding a sodium leak channel was not demonstrated until 2007 (Gilon and Rorsman, 2009) These channels allow the passive flow of sodium (and other cations) across the membrane and are thought to regulate the activity of rhythmically firing neurons through their modulation of the neuronal resting potential (Lu et al, 2007). They enhance excitability because the Na+ that they leak into the cell depolarizes the membrane potential shifting it toward the activation threshold of voltage-gated Na+ channels (Nav). These effects can cause a pacemaker neuron to fire continuously
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