Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function

Foote, Kendall M.; Lyman, Kyle A.; Han, Ye; Michailidis, Ioannis E.; Heuermann, Robert J.; Mandikian, Danielle; Trimmer, James S.; Swanson, Geoffrey T.; Chetkovich, Dane M.

doi:10.1074/jbc.ra119.010027

Cited by 22 publications

(34 citation statements)

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“…CaMKII activity is necessary for the DDE of HCN1 channels in CA1 and CaMKII activity is reduced in a rat KA model of TLE [54]. KA-mediated status epilepticus leads to a reduction in phosphorylation of a key serine residue of TRIP8b in a CaMKII consensus sequence, suggesting that this alteration may be mechanistically involved in mislocalization of HCN channels in TLE [54]. Overall, there is evidence suggesting that impaired TRIP8b function explains some of the HCN channel deficits observed in TLE.…”

Section: Major Depressive Disorder (Mdd)mentioning

confidence: 94%

“…Post-translational modifications of TRIP8b provide an additional layer of regulation that is beginning to be explored. Foote et al identified a serine residue within the CNBD-binding domain of TRIP8b that is phosphorylated by CaMKII and PKA (Figure 3(a)) [54]. Phosphorylation of this site has been observed for isoform 1a-4 and increases the strength of HCN channel binding leading to differences in HCN channel voltage dependence.…”

Section: Trip8b(1a-4)mentioning

confidence: 99%

“…Phosphorylation of this site has been observed for isoform 1a-4 and increases the strength of HCN channel binding leading to differences in HCN channel voltage dependence. This phosphorylation occurs within the distal dendrites of CA1 pyramidal and layer 5 neocortical cells raising the possibility that it may be involved in regulating trafficking as well [54].…”

Section: Trip8b(1a-4)mentioning

confidence: 99%

“…Studies have either reported a global loss of HCN1 expression [90,91,95] or a loss specifically in the distal dendrites that correlates with reduced TRIP8b interaction [89]. Some authors have attributed the loss of HCN1 protein to transcriptional repression [90,96] while others cite posttranslational modifications of HCN channels and TRIP8b [54,97]. CaMKII activity is necessary for the DDE of HCN1 channels in CA1 and CaMKII activity is reduced in a rat KA model of TLE [54].…”

Section: Major Depressive Disorder (Mdd)mentioning

confidence: 99%

“…Some authors have attributed the loss of HCN1 protein to transcriptional repression [90,96] while others cite posttranslational modifications of HCN channels and TRIP8b [54,97]. CaMKII activity is necessary for the DDE of HCN1 channels in CA1 and CaMKII activity is reduced in a rat KA model of TLE [54]. KA-mediated status epilepticus leads to a reduction in phosphorylation of a key serine residue of TRIP8b in a CaMKII consensus sequence, suggesting that this alteration may be mechanistically involved in mislocalization of HCN channels in TLE [54].…”

Section: Major Depressive Disorder (Mdd)mentioning

confidence: 99%

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The structure and function of TRIP8b, an auxiliary subunit of hyperpolarization-activated cyclic-nucleotide gated channels

et al. 2020

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Chetkovich (2020) The structure and function of TRIP8b, an auxiliary subunit of hyperpolarization-activated cyclicnucleotide gated channels, Channels, 14:1, 110-122, ABSTRACTHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed throughout the mammalian central nervous system (CNS). These channels have been implicated in a wide range of diseases, including Major Depressive Disorder and multiple subtypes of epilepsy. The diversity of functions that HCN channels perform is in part attributable to differences in their subcellular localization. To facilitate a broad range of subcellular distributions, HCN channels are bound by auxiliary subunits that regulate surface trafficking and channel function. One of the best studied auxiliary subunits is tetratricopeptide-repeat containing, Rab8b-interacting protein (TRIP8b). TRIP8b is an extensively alternatively spliced protein whose only known function is to regulate HCN channels. TRIP8b binds to HCN pore-forming subunits at multiple interaction sites that differentially regulate HCN channel function and subcellular distribution. In this review, we summarize what is currently known about the structure and function of TRIP8b isoforms with an emphasis on the role of this auxiliary subunit in health and disease. ARTICLE HISTORY

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Section: Major Depressive Disorder (Mdd)mentioning

confidence: 94%

Section: Trip8b(1a-4)mentioning

confidence: 99%

Section: Trip8b(1a-4)mentioning

confidence: 99%