The HCN1 hyperpolarization-activated cyclic nucleotide regulated cation channel regulates the electrical activity of several types of neurons in the brain and spinal cord. Whereas forebrain-restricted HCN1 knockout mice show an improvement in hippocampal-dependent spatial learning and memory, the mice also have an enhanced susceptibility to seizures. In both humans and wild-type mice an initial precipitating seizure alters HCN1 expression, which is thought to contribute to development of epilepsy. One striking feature of HCN1 is that the channel plays distinct physiological roles in different neuron as a result of its differential targeting to distinct neuronal compartments. Whereas HCN1 is targeted to distal dendrites in hippocampal CA1 pyramidal neurons, the channel is targeted to presynaptic terminals in inhibitory basket cells. Moreover the pattern of channel expression is dynamic. Following a seizure, HCN1 becomes mislocalized in CA1 neurons, appearing in the soma instead of dendrites. How can a single macromolecule be differentially targeted to distinct locales based on neural identity? What signaling mechanisms might be important in regulating channel location? HCN1 channel expression and function are powerfully regulated by a brain-specific auxiliary subunit of HCN1 termed TRIP8b. The brain contains at least ten different TRIP8b splice variants that differ in their cellular localization and effects on channel surface expression. Knockdown of all TRIP8b isoforms greatly reduces expression and prevents targeting of HCN1 to CA1 distal dendrites. In contrast a TRIP8b hypomorph mouse that lacks all but two TRIP8b isoforms normally expressed in brain shows normal levels of HCN1 expression and dendritic targeting in CA1. What is the role of TRIP8b in targeting HCN1 to its distinct subcellular locales in different neurons? Do different TRIP8b isoforms differentially target HCN1 in different neurons? What signals define the identity of neural compartments, such as the distal dendrites? Might such signals regulate HCN1 trafficking through phosphorylation? Answers to such questions will provide insight into the mechanisms by which neurons regulate their electrical signaling properties and how such mechanisms might provide novel disease substrates.
The electrical activity of nerve cells is controlled by specific ion channels, which are targeted to distinct regions of these cells. Changes in channel levels or localization can result in neurological disease, including epilepsy. This application is to identif the molecular mechanisms important for regulating the localization and expression of one particular channel critically important for brain function and disease.
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