Animal models suggest the TRIP8b-HCN interaction is a therapeutic target for major depressive disorder

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

doi:10.1080/14728222.2017.1287899

Cited by 24 publications

(20 citation statements)

References 14 publications

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“…Consistent with our western blot results, we measured a significant reduction in HCN1 expression in CA1 pyramidal neurons (Figure 3 b-d ). We next examined if TRIP8b, the HCN channel auxiliary subunit, was similarly changed since TRIP8b plays an important role in subcellular distribution and trafficking of HCN channels [48, 49], We measured a decrease in TRIP8b expression in CA1 pyramidal neurons by immunohistochemistry (Figure 3 e-g ) but the total protein level did not change as assessed by western blot (Suppl Figure 2 c,d ). Our data therefore indicate that there is a specific loss of both HCN1 and TRIP8b proteins in CA1 pyramidal neurons.…”

Section: Resultsmentioning

confidence: 99%

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

et al. 2018

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Neuroinflammation is consistently found in many neurological disorders, but whether or not the inflammatory response independently affects neuronal network properties is poorly understood. Here, we report that intracerebroventricular injection of the prototypical inflammatory molecule lipopolysaccharide (LPS) in rats triggered a strong and long lasting inflammatory response in hippocampal microglia associated with a concomitant up-regulation of Toll-like receptor (TLR4) in pyramidal and hilar neurons. This, in turn, was associated with a significant reduction of the dendritic hyperpolarization-activated cyclic-AMP gated channel type 1 (HCN1) protein level while Kv4.2 channels were unaltered as assessed by western blot. Immunohistochemistry confirmed the HCN1 decrease in CA1 pyramidal neurons and showed that these changes were associated with a reduction of TRIP8b, an auxiliary subunit for HCN channels implicated in channel subcellular localization and trafficking. At the physiological level, this effect translated into a 50% decrease in HCN1-mediated currents (Ih) measured in the distal dendrites of hippocampal CA1 pyramidal cells. At the functional level, the band-pass filtering properties of dendrites in the theta frequency range (4-12 Hz) and their temporal summation properties were compromised. We conclude that neuroinflammation can independently trigger an acquired channelopathy in CA1 pyramidal cell dendrites that alters their integrative properties. By directly changing cellular function, this phenomenon may participate in the phenotypic expression of various brain diseases.

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Section: Resultsmentioning

confidence: 99%

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

et al. 2018

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“…As such, both HCN and TRIP8b are potential targets for new antidepressant treatments, although it may ultimately be the case that manipulating either of these molecular targets has broader effects in promoting active coping behavior (Lyman et al . ).…”

Section: Discussionmentioning

confidence: 97%

HCN channels in the hippocampus regulate active coping behavior

Fisher

Han

Lyman

et al. 2018

Journal of Neurochemistry

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Active coping is an adaptive stress response that improves outcomes in medical and neuropsychiatric diseases. To date, most research into coping style has focused on neurotransmitter activity and little is known about the intrinsic excitability of neurons in the associated brain regions that facilitate coping. Previous studies have shown that HCN channels regulate neuronal excitability in pyramidal cells and that HCN channel current (I ) in the CA1 area increases with chronic mild stress. Reduction of I in the CA1 area leads to antidepressant-like behavior, and this region has been implicated in the regulation of coping style. We hypothesized that the antidepressant-like behavior achieved with CA1 knockdown of I is accompanied by increases in active coping. In this report, we found that global loss of TRIP8b, a necessary subunit for proper HCN channel localization in pyramidal cells, led to active coping behavior in numerous assays specific to coping style. We next employed a viral strategy using a dominant negative TRIP8b isoform to alter coping behavior by reducing HCN channel expression. This approach led to a robust reduction in I in CA1 pyramidal neurons and an increase in active coping. Together, these results establish that changes in HCN channel function in CA1 influences coping style.

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“…The interaction between TRIP8b and HCN channels has been identified as a therapeutic target for the treatment of major depressive disorder (25,33,43,44). The TPR domains of TRIP8b were initially considered an attractive target because of the accessible ligand-binding pocket (14), but the observations provided here indicate that disrupting the CNBD binding site will also inhibit TRIP8b function.…”

Section: Trip8b Allosterismmentioning

confidence: 93%

Allostery between two binding sites in the ion channel subunit TRIP8b confers binding specificity to HCN channels

Lyman

Han

Heuermann

et al. 2017

Journal of Biological Chemistry

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Tetratricopeptide repeat (TPR) domains are ubiquitous structural motifs that mediate protein-protein interactions. For example, the TPR domains in the peroxisomal import receptor PEX5 enable binding to a range of type 1 peroxisomal targeting signal motifs. A homolog of PEX5, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), binds to and functions as an auxiliary subunit of hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Given the similarity between TRIP8b and PEX5, this difference in function raises the question of what mechanism accounts for their binding specificity. In this report, we found that the cyclic nucleotide-binding domain and the C terminus of the HCN channel are critical for conferring specificity to TRIP8b binding. We show that TRIP8b binds the HCN cyclic nucleotide-binding domain through a 37-residue domain and the HCN C terminus through the TPR domains. Using a combination of fluorescence polarization- and co-immunoprecipitation-based assays, we establish that binding at either site increases affinity at the other. Thus, allosteric coupling of the TRIP8b TPR domains both promotes binding to HCN channels and limits binding to type 1 peroxisomal targeting signal substrates. These results raise the possibility that other TPR domains may be similarly influenced by allosteric mechanisms as a general feature of protein-protein interactions.

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Animal models suggest the TRIP8b-HCN interaction is a therapeutic target for major depressive disorder

Cited by 24 publications

References 14 publications

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

HCN channels in the hippocampus regulate active coping behavior

Allostery between two binding sites in the ion channel subunit TRIP8b confers binding specificity to HCN channels

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