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

Han, Ye; Lyman, Kyle A.; Foote, Kendall M.; Chetkovich, Dane M.

doi:10.1080/19336950.2020.1740501

Cited by 24 publications

(28 citation statements)

References 111 publications

(210 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, some variants of unknown significance have been reported, which indicate that existing dysfunctions may produce more information in the future (DiFrancesco et al, 2019 ). TRIP8b is a type of voltage-dependent cation channel that is modulated by direct cAMP binding, and it interacts with the C-terminal and CNBD of HCN channels to control channel trafficking or gating (Han et al, 2020 ). TRIP8b promotes HCN channel expression and enhances Ih current (Lewis et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Kessi

Peng

Duan

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

BackgroundHyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy.ObjectivesThis systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype–phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets.MethodsThe review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021.ResultsWe identified pathogenic variants of HCN1 (n = 24), HCN2 (n = 8), HCN3 (n = 2), and HCN4 (n = 6) that were associated with epilepsy in 74 cases (43 HCN1, 20 HCN2, 2 HCN3, and 9 HCN4). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising HCN1 (n = 4), HCN2 (n = 2), HCN3 (n = 2), and HCN4 (n = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults (n = 10) than children (n = 2). HCN1 variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as HCN2 variants p.S632W and delPPP (p.719–721), were associated with different phenotypes. HCN1 p.L157V and HCN4 p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers.ConclusionWe recommend clinicians to include HCN genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.

show abstract

Section: Resultsmentioning

confidence: 99%

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Kessi

Peng

Duan

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Furthermore, some paralogizations have led to paralogs of PEX proteins that may no longer function in peroxisome biology. For instance, vertebrates express a PEX5 paralog called PEX5R (TRIP8b), whose only known function is the regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels – key modulators of neuronal activity ( Han et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Comparative Genomics of Peroxisome Biogenesis Proteins: Making Sense of the PEX Proteins

Jansen

Santana-Molina

Noort

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

PEX genes encode proteins involved in peroxisome biogenesis and proliferation. Using a comparative genomics approach, we clarify the evolutionary relationships between the 37 known PEX proteins in a representative set of eukaryotes, including all common model organisms, pathogenic unicellular eukaryotes and human. A large number of previously unknown PEX orthologs were identified. We analyzed all PEX proteins, their conservation and domain architecture and defined the core set of PEX proteins that is required to make a peroxisome. The molecular processes in peroxisome biogenesis in different organisms were put into context, showing that peroxisomes are not static organelles in eukaryotic evolution. Organisms that lack peroxisomes still contain a few PEX proteins, which probably play a role in alternative processes. Finally, the relationships between PEX proteins of two large families, the Pex11 and Pex23 families, were analyzed, thereby contributing to the understanding of their complicated and sometimes incorrect nomenclature. We provide an exhaustive overview of this important eukaryotic organelle.

show abstract

“…The Pex5-related proteins may represent paralogs of Pex5, which may no longer function in peroxisomal matrix protein import. PEX5-related proteins are found in other vertebrates; PEX5R/TRIP8b (tetratrico-peptide-repeat containing, Rab8b-interacting protein) is involved in the regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the mammalian central nervous system ( Han et al, 2020 ). Although PEX5R can bind PTS1-containing proteins in vitro ( Amery et al, 2001 ), there is currently no evidence for a role in peroxisome biogenesis as PEX5R does not complement loss of PEX5.…”

Section: Resultsmentioning

confidence: 99%

Insights Into the Peroxisomal Protein Inventory of Zebrafish

et al. 2022

View full text Add to dashboard Cite

Peroxisomes are ubiquitous, oxidative subcellular organelles with important functions in cellular lipid metabolism and redox homeostasis. Loss of peroxisomal functions causes severe disorders with developmental and neurological abnormalities. Zebrafish are emerging as an attractive vertebrate model to study peroxisomal disorders as well as cellular lipid metabolism. Here, we combined bioinformatics analyses with molecular cell biology and reveal the first comprehensive inventory of Danio rerio peroxisomal proteins, which we systematically compared with those of human peroxisomes. Through bioinformatics analysis of all PTS1-carrying proteins, we demonstrate that D. rerio lacks two well-known mammalian peroxisomal proteins (BAAT and ZADH2/PTGR3), but possesses a putative peroxisomal malate synthase (Mlsl) and verified differences in the presence of purine degrading enzymes. Furthermore, we revealed novel candidate peroxisomal proteins in D. rerio, whose function and localisation is discussed. Our findings confirm the suitability of zebrafish as a vertebrate model for peroxisome research and open possibilities for the study of novel peroxisomal candidate proteins in zebrafish and humans.

show abstract

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

Cited by 24 publications

References 111 publications

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Comparative Genomics of Peroxisome Biogenesis Proteins: Making Sense of the PEX Proteins

Insights Into the Peroxisomal Protein Inventory of Zebrafish

Contact Info

Product

Resources

About