IndraLab
Statements
sparser
"Taken together, these results indicated a mechanism of dual binding of TRIP8b with HCN1 whereby the combination of both sets of TPR domains is required to bind to the C-terminal tripeptide of HCN1 (–SNL), while the first TPR set with 58 amino acid residues N-terminal to the TPR domains was required to bind to HCN1 CNBD ."
sparser
"In contrast, binding at the downstream interaction site serves to stabilize the C-terminal domain of TRIP8b, allowing for optimal interaction between HCN1 and TRIP8b as well as for proper assembly of the molecular complexes that mediate the effects of TRIP8b on HCN1 channel trafficking."
reach
"These results, together with the robust biochemical association between HCN1 and TRIP8b in vivo (XREF_FIG) and the tight co-localization of the two proteins in the distal dendrites of cortical pyramidal neurons, strongly suggest that TRIP8b plays an important role in the regulation of I h in the brain."
sparser
"Alterations in TRIP8b-HCN1 interactions may also contribute to the maladaptive changes in HCN1 expression associated with seizures that is thought to contribute to the development of epilepsy ( xref ; xref ; xref ; xref ; xref ; xref ), an effect that is, in part, due to a redistribution of HCN1 from the distal dendrites to the soma of CA1 neurons ( xref )."
sparser
"To tease out the molecular foundations for these different effects of TRIP8b on HCN channel gating and surface expression, we, along with our collaborators (as well as the work of an independent group) have recently demonstrated that the interaction between TRIP8b and HCN1 channels involves two separate molecular interfaces that differentially influence channel gating and surface expression [ xref , xref ]."
sparser
"Thus, altered expression of HCN channels or I h is a phenomenon regularly observed in models of experimental epilepsy xref , xref , xref , xref , xref , xref , xref , xref , and even in human epilepsy xref , and altered interaction of HCN1 with TRIP8b could be a critical mechanism contributing to this phenomen xref ."
reach
"Because different isoforms of TRIP8b elicited different effects on HCN1 mediated current and surface expression in HEK293T cells, yet all TRIP8b isoforms bind to HCN1, we tested if the differential structure of the isoforms might govern their effects on h channel trafficking and subcellular localization in neurons."
reach
"Taken together, these results indicated a mechanism of dual binding of TRIP8b with HCN1 whereby the combination of both sets of TPR domains is required to bind to the C-terminal tripeptide of HCN1 (-SNL), while the first TPR set with 58 amino acid residues N-terminal to the TPR domains was required to bind to HCN1 CNBD."
sparser
"We find that HCN1 and TRIP8b interact at two distinct sites: an upstream site where the C-linker/cyclic nucleotide-binding domain of HCN1 interacts with an 80 aa domain in the conserved central core of TRIP8b; and a downstream site where the C-terminal SNL (Ser-Asn-Leu) tripeptide of the channel interacts with the tetratricopeptide repeat domain of TRIP8b."
reach
"Given the association between TRIP8b and HCN1 in regions of the mouse brain known to possess high levels of h channels and I h, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR it was surprising that Santoro et al. found coexpression of HCN1 or HCN2 with TRIP8b led to dramatic downregulation of I h and surface associated h channel protein in oocytes as well as in cultured hippocampal neurons, with the decrease in I h dependent upon the presence of the h channel C-terminal tripeptide."
reach
"In contrast, binding at the downstream interaction site serves to stabilize the C-terminal domain of TRIP8b, allowing for optimal interaction between HCN1 and TRIP8b as well as for proper assembly of the molecular complexes that mediate the effects of TRIP8b on HCN1 channel trafficking."
sparser
"Immunohistochemistry for TRIP8b and HCN1 demonstrated exquisite costaining in distal dendrites of CA1 and layer V neocortical pyramidal neurons, implying that TRIP8b’s association with at least HCN1 may play a functional role in vivo, an implication strengthened by the finding that TRIP8b enrichment in the distal dendrites of layer V neurons in the cortex was abolished in the HCN1 −/− mouse."
sparser
"Of further interest, the activation of I h in CA1 distal apical dendrites is shifted by ∼6 mV to more negative voltages than those required to activate I h in more proximal regions of the dendrite ( xref ), an effect that might be explained by a more prominent association of TRIP8b with HCN1 channels in the distal dendrites, where TRIP8b and HCN1 co-localization is tightest ( xref )."
reach
"Our findings that mutations that perturb the downstream interaction between TRIP8b and HCN1 differentially alter the functional consequences of residual binding at the upstream site have interesting implications for the dynamic regulation of the TRIP8b and HCN1 interaction in vivo."