RESEARCH HIGHLIGHTS ION CHANNELS These studies add HCN channels to the list of ion channels that are regulated by auxiliary subunits and A regulatory sidekick show that specific TRIP8b isoforms can differentially regulate Ih and thus The trafficking and function of changes in HCN channel surface control intrinsic neuronal excitability. many ion channels are regulated by expression resulting from alterations Katherine Whalley subunits that do not contribute to the in HCN subunit trafficking. pore-forming core of the channel. TRIP8b also altered HCN ORIGINAL RESEARCH PAPERS Lewis, A. S. et al. Alternatively spliced isoforms of TRIP8b Three recent papers reveal a role for channel gating. Santoro et al. and differentially control h channel trafficking and cytoplasmic tetratricopeptide repeat- Zolles et al. showed that TRIP8b function. J. Neurosci. 29, 6250–6265 (2009) | containing Rab8b-interacting protein slowed channel opening and acceler- Santoro, B. et al. TRIP8b splice variants form a family of auxiliary subunits that regulate gating (TRIP8b, also known as PEX5R and ated channel closing. Furthermore, and trafficking of HCN channels in the brain. PEX5Rp) as a regulatory auxiliary Lewis et al. and Santoro et al. found Neuron 62, 802–813 (2009) | Zolles, G. et al. Association with the auxiliary subunit PEX5R/ subunit of hyperpolarization- that co-expressing TRIP8b with Trip8b controls responsiveness of HCN channels activated cyclic nucleotide-gated HCN subunits shifted the membrane to cAMP and adrenergic stimulation. Neuron 62, (HCN) channels. potential threshold for HCN channel 814–825 (2009) FURTHER READING Santoro, B. et al. The HCN channel pore, consist- activation to more hyperpolarized Regulation of HCN channel surface expression ing of HCN1–HCN4 subunits, opens potentials, regardless of the isoform by a novel C-terminal protein-protein at negative membrane potentials and tested. interaction. J. Neurosci. 24, 10750–10762 (2004) | Shin, M. et al. Mislocalization of h channel generates the Ih current that regu- How does TRIP8b affect channel subunits underlies h channelopathy in temporal lates intrinsic neuronal excitability. gating? Cyclic AMP shifts the activa- lobe epilepsy. Neurobiol. Dis. 32, 26–36 (2008) Variability in Ih has been reported tion threshold of HCN to less hyper- and abnormalities in this current are polarized potentials, suggesting that linked to epilepsy. The three groups TRIP8b might counteract this facili- therefore investigated the modulation tation. Indeed, TRIP8b inhibited the of HCN channels. Previous studies, effects of exogenous cAMP on HCN2 using yeast two-hybrid screening and HCN4 channels in excised and co-immunoprecipitation (see inside-out patches (in which the Further Reading), indicated that inner surface of the cell membrane is TRIP8b interacts with HCN proteins. exposed to experimental treatments; Here, this association was confirmed Zolles et al.). Furthermore, Santoro in mouse and rat brain extracts. et al. showed that mutations in cAMP Moreover, proteomic analysis by binding sites on HCN1 abolished Zolles et al. indicated that TRIP8b TRIP8b’s effects on gating in intact is potentially the major endogenous cells. auxiliary HCN channel subunit in Different regions of TRIP8b the mammalian brain. contribute to its effects. Lewis et al. Exons 1–4 of TRIP8b undergo showed that two sites in TRIP8b’s alternative splicing and Lewis et al. conserved regions bind to distinct and Santoro et al. identified nine sites in HCN1. Zolles et al. found TRIP8b splice variants in the rat and that conserved regions in the amino- mouse brain. When co-expressed terminal core domain are crucial for with HCN1 in HEK293T cells, TRIP8b’s effects on gating. Moreover, Xenopus laevis oocytes or hippocam- as shown by Santoro et al., motifs pal neurons these variants differen- in exons 2 and 5 of the extreme tially upregulated or downregulated N terminus govern the protein’s Ih. These effects were mediated by effects on surface expression. NATURE REVIEWS | NEUROSCIENCE VOLUME 10 | AUGUST 2009 © 2009 Macmillan Publishers Limited. All rights reserved.