The TRIP8b-HCN Interaction as a Therapeutic TargetPublic Deposited
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed in the heart and central nervous system where they regulate membrane excitability. Recently, inhibiting HCN channels in the hippocampus has been identified as a possible therapeutic intervention for the treatment of Major Depressive Disorder (MDD). However, based on the high expression level of HCN channels in the heart, antagonists of the channel are unlikely to be useful as antidepressants without causing substantial cardiac side effects. To circumvent this issue, our lab has recently proposed disrupting the interaction between HCN channels and a brain-specific auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Given that TRIP8b is only expressed in the brain, small molecule mediated disruption of TRIP8b binding with HCN would circumvent HCN channels in the heart. In support of this strategy, we have recently used a viral approach to demonstrate that disruption of TRIP8b mediated HCN channel trafficking in the CA1 region is sufficient to produce antidepressant-like behavioral changes in mice. In addition to neurons, both TRIP8b and HCN channels are expressed in cells of the oligodendrocyte lineage, hence any therapy that disrupts the TRIP8b-HCN interaction could also affect oligodendrocytes. In this thesis, we will investigate the function of TRIP8b and HCN in the oligodendrocyte lineage in order to determine if therapeutically targeting the TRIP8b-HCN interaction could lead to significant side effects (Chapter 2). We will next investigate the binding of TRIP8b to HCN channels (Chapter 3) and develop a high throughput screen for identifying small molecule inhibitors of this interaction (Chapter 4). These studies provide an important foundation for considering the TRIP8b-HCN interaction as a therapeutic target.