2011
DOI: 10.1523/jneurosci.5707-10.2011
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TRIP8b Regulates HCN1 Channel Trafficking and Gating through Two Distinct C-Terminal Interaction Sites

Abstract: Hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the brain associate with their auxiliary subunit TRIP8b (also known as PEX5R), a cytoplasmic protein expressed as a family of alternatively spliced isoforms. Recent in vitro and in vivo studies have shown that association of TRIP8b with HCN subunits both inhibits channel opening and alters channel membrane trafficking, with some splice variants increasing and others decreasing channel surface expression. Here, we address the structural b… Show more

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Cited by 76 publications
(128 citation statements)
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References 20 publications
(73 reference statements)
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“…We have previously shown that TRIP8b core , an 80-aa sequence located in the TRIP8b protein core that directly interacts with the C-linker/CNBD region of HCN channels, is necessary and sufficient to prevent all of the effects of cAMP on the channel (10,11). TRIP8b core decreases both the sensitivity of the channel to cAMP [half maximal concentration (k 1/2 )] and the efficacy of cAMP in inducing channel opening [half activation voltage (V 1/2 )]; conversely, cAMP binding inhibits these actions of TRIP8b.…”
mentioning
confidence: 99%
“…We have previously shown that TRIP8b core , an 80-aa sequence located in the TRIP8b protein core that directly interacts with the C-linker/CNBD region of HCN channels, is necessary and sufficient to prevent all of the effects of cAMP on the channel (10,11). TRIP8b core decreases both the sensitivity of the channel to cAMP [half maximal concentration (k 1/2 )] and the efficacy of cAMP in inducing channel opening [half activation voltage (V 1/2 )]; conversely, cAMP binding inhibits these actions of TRIP8b.…”
mentioning
confidence: 99%
“…This zone has been described in HCN channels to be flexible and able to absorb conformational changes (Taraska et al, 2009). Furthermore, evidence is available in HCN channels that the C-linker E9 and F9 helices play a role in proper folding of the CNBD (Santoro et al, 2011). It is also relevant that, in HCN channels expressed in mouse brain, the C-linker E9 and F9 helices and the CNBD form a site that binds auxiliary subunits, named TRIP8b or PEX5R, which play a role in the surface expression (and activity) of the channel (Santoro et al, 2011;Han et al, 2011;Bankston et al, 2012).…”
Section: Discussionmentioning
confidence: 94%
“…Furthermore, evidence is available in HCN channels that the C-linker E9 and F9 helices play a role in proper folding of the CNBD (Santoro et al, 2011). It is also relevant that, in HCN channels expressed in mouse brain, the C-linker E9 and F9 helices and the CNBD form a site that binds auxiliary subunits, named TRIP8b or PEX5R, which play a role in the surface expression (and activity) of the channel (Santoro et al, 2011;Han et al, 2011;Bankston et al, 2012). We thus hypothesize that, in KAT2, the short sequence that connects the C-linker F9 helix to the CNBD and comprises the Val-381 and Ser-382 residues plays a role in the folding of the structure formed by the C-linker and CNBD (as in HCN channels) and that substituting Val-381 by a Phe or Ser-382 by a Pro compromises the proper folding of this structure.…”
Section: Discussionmentioning
confidence: 99%
“…1A) HCN in a 1:1 stoichiometry and has profound effects on channel trafficking and gating (8)(9)(10). The C-terminal tetratricopeptide repeat (TPR) domain of TRIP8b interacts with the final three amino acids of HCN (SNL in HCN1, -2, and -4; ANM in HCN3) and this interaction affects channel trafficking (9,11,12). A core domain of TRIP8b upstream of the TPR domain interacts with the CNBD of HCN, affecting trafficking, but also interfering with the ability of cAMP to activate the channel (11)(12)(13).…”
Section: Trip8b Affects Camp Action Allostericallymentioning
confidence: 99%
“…The C-terminal tetratricopeptide repeat (TPR) domain of TRIP8b interacts with the final three amino acids of HCN (SNL in HCN1, -2, and -4; ANM in HCN3) and this interaction affects channel trafficking (9,11,12). A core domain of TRIP8b upstream of the TPR domain interacts with the CNBD of HCN, affecting trafficking, but also interfering with the ability of cAMP to activate the channel (11)(12)(13). Although the details of the TPR interaction with the distal C terminus of HCN are known at the atomic level, the nature of the interaction between the TRIP8b core domain and the CNBD has not been determined previously (8).…”
Section: Trip8b Affects Camp Action Allostericallymentioning
confidence: 99%