IndraLab

Statements


PEX5L decreases the amount of HCN1. 26 / 26
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"In agreement with this notion, TRIP8b isoforms that prevent HCN1 expression have been suggested to be located in adult hippocampal CA1 axons."

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"TRIP8b (1a) also decreases expression of HCN1, although the reduction in current density is ~ 10-fold, significantly less than the effect of TRIP8b (1b-2) or TRIP8b (1b-2-4)."

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"TRIP8b 1a was reported to inhibit the axonal localization of HCN1, and may up- or down-regulate HCN1 surface expression depending on the cell type in which it is expressed."

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"Specifically, TRIP8b (1a-4) increases HCN1 surface expression (Zolles et al., 2009), whereas TRIP8b (1b-2) inhibits the transport of HCN1 channel from the plasma membrane (Biel et al., 2009), thereby strongly downregulating HCN1 expression on the cell membrane."

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"Our mutagenesis experiments establish the role of the YXXL and EXXXLL consensus AP binding site motifs, present in exon 2 and exon 5, respectively, in the action of distinct TRIP8b isoforms to decrease the surface expression of HCN1 channels."

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"In particular, TRIP8b(1a) suppresses HCN1 expression in axons, while TRIP8b(1a-4) enhances HCN1 expression in dendrites (Piskorowski et al., 2011; Wilkars et al., 2012)."

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"Consequently, TRIP8b (1a-4) and TRIP8b (1b-2) proteins are downregulated and upregulated, respectively, thereby reducing the surface expression of HCN1 and increasing neuronal excitability."

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"In contrast, TRIP8b (1a) decreases HCN1 surface expression by 10-fold, and both TRIP8b (1b-2) and TRIP8b (1b-2-4) virtually eliminate channel surface expression."

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"As mentioned above, these isoforms exert distinct effects on HCN1 trafficking : TRIP8b (1a-4) strongly increases HCN1 surface expression; TRIP8b (1a) produces a ~ 10 fold decrease of HCN1 surface expression in Xenopus oocytes but enhances HCN1 expression in a mammalian cell line; and TRIP8b (1b-2) essentially abolishes surface expression in both oocytes and mammalian cells (> 50-fold decrease) by promoting channel endocytosis."

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"Deletion of the SNL tripeptide caused a selective impairment in the downregulation of HCN1 surface expression by either TRIP8b (1a) or TRIP8b (1b-2)."

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"Whereas the SNL deletion only partially inhibited channel downregulation with TRIP8b (1b-2), it fully blocked the effect of TRIP8b (1a) to decrease HCN1 expression."

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"Surprisingly, both of these truncated TRIP8b isoforms efficiently downregulated HCN1 surface expression, very similar to the effects of the wild-type isoforms (XREF_FIG)."

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"Differential phosphorylation may also explain why TRIP8b (1a) downregulates HCN1 surface expression in Xenopus oocytes whereas it upregulates HCN1 in a mammalian cell line."

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"Thus, the decreased ability of TRIP8b (1b-2) to abolish HCN1 surface expression seen with truncation of the channel 's SNL tripeptide is rescued upon truncation of the entire non conserved C-terminus of HCN1 (XREF_FIG)."

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"Specifically, PEX5L (1b-2–4) reduces HCN1 expression, and (1b-2) results in the sequestering of HCN1 to intracellular puncta in hippocampal CA1 (Lewis et al., 2009; Santoro et al., 2009)."

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"Independently, PEX5L (1a) prevents the axonal expression of HCN1, while PEX5L (1a-4) localizes HCN1 to the distal dendritic layer of CA1 (Lewis et al., 2009; Santoro et al., 2009; Piskorowski et al., 2011)."

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"Of the two remaining hippocampal TRIP8b isoforms, TRIP8b (1a-4) promoted HCN1 surface expression in dendrites whereas TRIP8b (1a) suppressed HCN1 misexpression in axons."

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"TRIP8b (1b-2) overexpression causes a near complete loss of HCN1 surface expression and Ih, in both heterologous cells and hippocampal neurons."

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"The effect of TRIP8b (1a) depends on cellular context, causing a 10-fold decrease in HCN1 surface expression in oocytes while enhancing HCN1 expression in HEK293 cells."

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"Knock-down of TRIP8b impaired the expression of EGFP-HCN1 in CA1 distal dendrites."

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"As downregulation of TRIP8b with siRNA decreases HCN1 surface expression, the HCN1 DeltaSNL results further indicate that the actions of TRIP8b to enable proper surface membrane expression and direct distal dendritic targeting of HCN1 are dissociable functions."

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"These immunohistochemistry data, together with previous findings that TRIP8b (1a-4) promotes HCN1 surface expression in heterologous cells, suggest that TRIP8b (1a-4) is likely to be a key TRIP8b isoform that promotes the surface expression and efficient targeting of HCN1 to the CA1 distal dendrites."

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"Given that TRIP8b (1a) downregulates HCN1 surface expression in Xenopus oocytes, our findings suggest that TRIP8b (1a) may act to suppress HCN1 channel misexpression in CA1 neuron axons."

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"Downregulation of HCN1 surface expression by TRIP8b (1a) in Xenopus oocytes is dependent on the presence of a dileucine adaptor protein trafficking motif in the N-terminal domain of the TRIP8b protein."

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"In particular, we suggest that TRIP8b (1a) largely prevents HCN1 misexpression in axons whereas TRIP8b (1a-4) enhances channel surface expression and ensures proper dendritic targeting."

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"In addition to confirming these in vitro results, we found that downregulation of TRIP8b in vivo inhibited HCN1 membrane expression and Ih in CA1 neurons."