TRIP(8B)Ing up and Down HCN Channel Gating and Trafficking

Abstract

The proper neuronal functioning of ion channels depends on their correct targeting to distinct polarized neuronal compartments, where the channels often mediate highly specific functions. HCN1 channels, which underlie the hyperpolarization-activated cation current (Ih) in many types of neurons, are targeted to the distal apical dendrites of hippocampal CA1 pyramidal neurons, where they regulate the integration of synaptic inputs and control excitability. Results from our laboratory and others indicate that the cytoplasmic protein TRIP8b is the major auxiliary subunit of HCN1 channels in the brain, where it plays an important role in regulating HCN1 function, expression and localization. TRIP8b undergoes extensive alternative splicing at its N-terminus, with at least 10 splice variants detected in brain. All splice variants interact strongly with the C-terminus of all four HCN channel isoforms (HCN1-4) at two different interaction surfaces. Whereas all TRIP8b isoforms inhibit channel gating by antagonizing the normal action of cAMP to facilitate opening, the various isoforms have distinct effects on channel trafficking. We identified two splice isoforms with opposing actions on HCN1 surface expression and distinct subcellular locales that are critical for HCN1 dendritic targeting. Our more recent results have identified the structural and functional bases for many of the regulatory actions of TRIP8b.