IndraLab

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PEX5L activates HCN1. 14 / 14
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"With respect to these four mechanisms, perhaps the simplest view is that TRIP8b (1a-4) promotes HCN1 distal dendritic targeting through mechanism 1 whereas TRIP8b (1a) prevents axonal mislocalization through mechanism 2."

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"For example, the brain-specific HCN channel auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) supports dendritic enrichment of HCN1 via intracellular interactions (Piskorowski et al., 2011)."

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"The upregulation or downregulation of I h density produced by these newly characterized TRIP8b isoforms appear to be caused largely by changes in channel surface expression, similar to our previous finding that TRIP8b (1b-2) promotes endocytosis of surface HCN1 channels."

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"Reduction of TRIP8b disrupted HCN1 protein trafficking in CA1 pyramidal neurons."

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"Moreover, in vivo expression of TRIP8b (1a-4) produces a marked increase in the level of GFP tagged HCN1 protein associated with the dendritic plasma membrane (XREF_FIG)."

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"However, TRIP8b alone is not sufficient for the distal enrichment of HCN1 channels as endogenous or exogenous expression of TRIP8b in dissociated hippocampal neuron cultures fails to target HCN1 to the PN distal dendrites."

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"Moreover, we found that TRIP8b (1a-4), which upregulates HCN1 in heterologous systems, is the key isoform involved in dendritic expression of HCN1."

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"However, the extent to which TRIP8b modulates HCN1 can vary."

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"Here we discuss two examples of how splicing can be used to ensure the proper localization of ion channels during critical developmental timepoints.The localization of hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1), a channel responsible for the I current that modulates action potential firing frequency, is mediated by the splicing of peroxisomal biogenesis factor 5 like (Pex5l; Santoro et al., 2004)."

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"In hippocampal neurons, coexpression of TRIP8b isoforms with HCN1 produced isoform specific changes of HCN1 localization."

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"Viral expression of TRIP8b siRNA, but not control siRNA, caused a marked redistribution of HCN1 in CA1 neurons, with a significant increase in channel staining in the somatic layer and proximal dendrites in SR, compared to uninfected neurons in the same slice (XREF_FIG)."

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"An increase in the expression of TRIP8b splice variants that cause HCN1 internalization could produce such a long-term downregulation of I h current density without altering total protein levels."

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"In accord, increasing cAMP levels in cells antagonized the up-regulation of HCN1 channels mediated by a TRIP8b construct binding the CNBD exclusively."

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"Indeed, we have previously shown that TRIP8b (1b-2) induces the near-complete internalization of HCN1 from the plasma membrane, resulting in an accumulation of channel protein in intracellular vesicles, a subset of which can be identified as early endosomes."