TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain.
Hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels, which generate the I(h) current, mediate a number of important brain functions. The HCN1 isoform regulates dendritic integration in cortical pyramidal neurons and provides an inhibitory constraint on both working memory in prefrontal cortex and spatial learning and memory in the hippocampus. Altered expression of HCN1 following seizures may contribute to the development of temporal lobe epilepsy. Yet the regulatory networks and pathways governing HCN channel expression and function in the brain are largely unknown. Here, we report the presence of nine alternative N-terminal splice forms of the brain-specific cytoplasmic protein TRIP8b and demonstrate the differential effects of six isoforms to downregulate or upregulate HCN1 surface expression. Furthermore, we find that all TRIP8b isoforms inhibit channel opening by shifting activation to more negative potentials. TRIP8b thus functions as an auxiliary subunit that provides a mechanism for the dynamic regulation of HCN1 channel expression and function.
Santoro
Bina
B
Department of Neuroscience, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
Piskorowski
Rebecca A
RA
Pian
Phillip
P
Hu
Lei
L
Liu
Haiying
H
Siegelbaum
Steven A
SA
D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D016384:Consensus Sequence; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000235:genetics*; D046911:Macromolecular Substances / Q000378:metabolism; D008564:Membrane Potentials / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014162:Transfection / Q000379:methods
D033962:Adaptor Protein Complex 2; D054815:Cyclic Nucleotide-Gated Cation Channels; C578666:Hcn1 protein, mouse; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D046911:Macromolecular Substances; D008565:Membrane Proteins; C523657:Pex5l protein, rat; D015221:Potassium Channels; D020033:Protein Isoforms; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins