Discovery of a small-molecule inhibitor of the TRIP8b–HCN interaction with efficacy in neurons

Han, Ye; Iyamu, Iredia D.; Clutter, Matthew R.; Mishra, Rama K.; Lyman, Kyle A.; Zhou, Chengwen; Michailidis, Ioannis E.; Xia, Maya; Hl, Sharma; Luan, Chi‐Hao; Schiltz, Gary E.; Chetkovich, Dane M.

doi:10.1016/j.jbc.2022.102069

Cited by 4 publications

(5 citation statements)

References 45 publications

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“…Brain penetrant isoform-specific HCN blockers have also been developed and were shown to protect against seizures in mice [ 36 ]. Small-molecule inhibitors of the TRIP8b-HCN interaction may provide more selective targeting of neuronal HCNs [ 78 ]. There is therefore an opportunity to target HCNs for the treatment of cocaine use disorder and other mental disorders such as depression.…”

Section: Discussionmentioning

confidence: 99%

cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement

Mu,

Liu,

et al. 2023

Mol Psychiatry

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Chronic cocaine exposure induces enduring neuroadaptations that facilitate motivated drug taking. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to modulate neuronal firing and pacemaker activity in ventral tegmental area (VTA) dopamine neurons. However, it remained unknown whether cocaine self-administration affects HCN channel function and whether HCN channel activity modulates motivated drug taking. We report that rat VTA dopamine neurons predominantly express Hcn3-4 mRNA, while VTA GABA neurons express Hcn1–4 mRNA. Both neuronal types display similar hyperpolarization-activated currents (Ih), which are facilitated by acute increases in cAMP. Acute cocaine application decreases voltage-dependent activation of Ih in VTA dopamine neurons, but not in GABA neurons. Unexpectedly, chronic cocaine self-administration results in enhanced Ih selectively in VTA dopamine neurons. This differential modulation of Ih currents is likely mediated by a D2 autoreceptor-induced decrease in cAMP as D2 (Drd2) mRNA is predominantly expressed in dopamine neurons, whereas D1 (Drd1) mRNA is barely detectable in the VTA. Moreover, chronically decreased cAMP via Gi-DREADD stimulation leads to an increase in Ih in VTA dopamine neurons and enhanced binding of HCN3/HCN4 with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit that is known to facilitate HCN channel surface trafficking. Finally, we show that systemic injection and intra-VTA infusion of the HCN blocker ivabradine reduces cocaine self-administration under a progressive ratio schedule and produces a downward shift of the cocaine dose-response curve. Our results suggest that cocaine self-administration induces an upregulation of Ih in VTA dopamine neurons, while HCN inhibition reduces the motivation for cocaine intake.

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Section: Discussionmentioning

confidence: 99%

cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement

Mu,

Liu,

et al. 2023

Mol Psychiatry

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“…Despite high expression levels, and the presence of subcellular regulation by TRIP8b, the precise function of HCN2 channels in oligodendrocyte lineage cells remains unknown. It is notable that loss of HCN2 in oligodendrocytes was not associated with an overt behavioral phenotype in the absence of EAE, suggesting the therapies directed at HCN channels [as has been suggested for the treatment of Major Depressive Disorder and delirium (Han et al, 2015(Han et al, , 2022Lyman et al, 2017a;Lyman, 2023)] are unlikely to cause adverse effects on oligodendrocytes.…”

Section: Trip8b Regulates Hcn2 Expression In Oligodendrocytesmentioning

confidence: 99%

Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes

Lyman,

Han,

Robinson

et al. 2024

Front. Cell. Neurosci.

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Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (Ih) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage. We observed that mice with a nonsense mutation in the Hcn2 gene (Hcn2ap/ap) have less white matter than their wild type counterparts with fewer OLG and fewer oligodendrocyte progenitor cells (OPCs). Hcn2ap/ap mice have severe motor impairments, although these deficits were not observed in mice with HCN2 conditionally eliminated only in oligodendrocytes (Cnpcre/+; Hcn2F/F). However, Cnpcre/+; Hcn2F/F mice develop motor impairments more rapidly in response to experimental autoimmune encephalomyelitis (EAE). We conclude that HCN2 channels in OLG may play a role in regulating metabolism.

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“…255 Moreover, there is ongoing research on peptides based on TRIP8b, an auxiliary subunit that regulates surface expression and modulates the cAMP sensitivity of HCN channels in the brain. [256][257][258][259] This includes the development of small molecules targeting the TRIP8b-HCN interaction, 260 as well as the design of shortened membrane-permeable versions of TRIP8b as tools for potential therapeutic use. 261 Given the crucial role of HCN channels in the development of neuronal and cardiac disease, the search for HCN-targeting drugs continues to be the subject of intensive research.…”

Section: Hcn Channels In Disease and Therapymentioning

confidence: 99%

Pacemaker Channels and the Chronotropic Response in Health and Disease

Hennis,

Piantoni,

Biel

et al. 2024

Circulation Research

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Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease—including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating β-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate–sensitive hyperpolarization–activated current (I f ) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate–dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.

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Discovery of a small-molecule inhibitor of the TRIP8b–HCN interaction with efficacy in neurons

Cited by 4 publications

References 45 publications

cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement

cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement

Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes

Pacemaker Channels and the Chronotropic Response in Health and Disease

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