) Potassium channels are widely involved in various physiological and pathological processes, including membrane excitability, body fluid regulation and cancer cell metastasis. We have previously shown that a voltage-gated potassium channel Kv1.1 acts as a molecular brake on adult neurogenesis in a cell-autonomous manner (Yang et al., 2012). In mammals, the majority of neurons in the central nervous system are born during the embryonic stage, and postnatal neurogenesis is limited to only a few brain regions, including the subgranular zone of the dentate gyrus. Postnatal neurogenesis is tightly regulated by a balance between cell renewal and differentiation to generate postnatally-born neurons. Given the importance of postnatal neurogenesis in learning and memory, my lab further explored the molecular and physiological mechanisms underlying Kv1.1-dependent postnatal neurogenesis. Our results demonstrate the importance of membrane excitability and ion channel expression in regulating neuronal progenitor cell proliferation. The post-hoc immunostaining and multinomial logistic regression analysis show that the neuronal progenitor cell membrane potentials are highly dynamic during postnatal neurogenesis. Although Kv1.1 is widely expressed in the dentate gyrus, including neurons and the neuronal progenitors, to our surprise, deleting Kv1.1 caused depolarization in the transit-amplifying type 2b neuronal progenitor cells. This depolarization was associated with increased neuronal progenitor cell proliferation mediated by the TrkB signaling pathway, as suppressing the TrkB signaling reduced the Kv1.1-dependent postnatal neurogenesis (Chou et al., 2021).
(2) Insulin secretion is under the tight control of circulating glucose. In pancreatic beta-cell, the cellular metabolic signals are converted into electrical activities by modulating the KATP channel activities. Since the pancreatic KATP channel plays a pivotal role in regulating insulin secretion, it is not surprising that KATP channel mutations cause metabolic disorders such as Neonatal Diabetes Mellitus (NDM) and Persistent Hyperinsulinemic Hypoglycemia in Infancy (PHHI). In 2017, our group reported a novel dominant form of PHHI, with a Val substitution for Ala at position 28 of the Kir6.2 peptide chain (A28V hKir6.2) (Yang et al., 2017). Our functional analysis shows that the A28V hKir6.2 mutation produces only minuscule KATP currents due to a trafficking defect that prevents surface expression. Next, we collaborated with Dr. Pei-Chun Chen at National Cheng- Kung University to investigate how this A28V hKir6.2 mutant impairs proper KATP channel trafficking (Lin et al., 2022a). Our biochemical studies showed that A28V hKir6.2 mutant KATP channels seem to escape the ER quality control and can still arrive at the Golgi apparatus; however, instead of moving forward to the plasma membrane, the mutant KATP channels make a detour towards proteasomes. This observation leads us to speculate that the majority of the mutant channels remained unglycosylated and stayed in the Golgi complex. Furthermore, we also showed that carbamazepine could serve as a chemical chaperone to rescue trafficking mutant KATP channels (Lin et al., 2022). Cryo-EM studies on KATP channels revealed that carbamazepine could stabilize the Kir6.2 N terminus within the SUR1 core, allowing it to act as a firm "handle" for assembling metastable mutant KATP channel complexes. Together, our findings suggest that carbamazepine, a pharmacochaperone, can be used for treating PHHI caused by trafficking KATP channel mutants.
(3) TALK1 channel is activated by the alkaline solutions, and it is specifically expressed in the pancreas. Previously, a multinational team, including the genetic and epidemiology group from IBMS, conducted a genome-wide association study that identified several single-nucleotide polymorphisms of the TALK1 to be associated with elevated risk for type 2 diabetes. Moreover, a Leu to Pro missense mutation at position 114 (TALK1-L114P) has recently been identified in a family with Maturity-Onset Diabetes of the Young (MODY). Nevertheless, the basic gating properties of TALK1 remain elusive despite the fact that this channel was identified two decades ago. Collaborating with Dr. Carmay Lim at our institute, we have shown that an arginine residue R233 located at the N-terminal end of transmembrane segment 4 distally regulates the orientation of the carbonyl group at the S1 potassium-binding site through an interacting network composed of residues on transmembrane segment 4, the pore helix domain 1, and the selectivity filter (Tsai et al., 2022). We further demonstrated that a gain-of-function TALK1 L114P mutant found in
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MODY patients increases the TALK1 current size by antagonizing the C-type gate near the selectivity filter. These mechanisms provide a crucial functional and structural basis for understanding the actions of WT and disease-causing mutant K2P channels and show potential targets for controlling TALK1 activities.
(4) Clinical studies have demonstrated the pathophysiological alterations in AD patients' central nervous system; however, it is still unclear whether AD pathology causes metabolic dysfunctions by impairing the hypothalamus, a critical brain region for energy homeostasis regulation. Collaborating with Dr. Huey-Jen Tsay at National Yang-Ming University, we found that AD- related pathology enhanced HFD-induced metabolic stresses (Lee et al., 2018). The HFD-fed AD mice were more obese (due to impaired leptin signaling in the hypothalamic arcuate nucleus, the key feeding-control center. The glucose homeostasis in HFD-fed AD mice was also impaired by inhibiting the insulin-induced glucose uptake in the brown adipose tissue. In conclusion, our study has provided evidence suggesting that the hypothalamus is the intersecting node between AD pathology and metabolic dysfunction.
(5) The limbic system includes the hypothalamus and hippocampus, which are functionally interconnected and involved in various innate behaviors, such as energy metabolism, social hierarchy, and memory formation. Collaborating with Drs. Yu-Ju Chou and Tsung-Han Kuo at the National Tsing-Hua University, our team has identified a strong cross-species correlation between social hierarchy and memory by tuning memory-related genes in the hippocampus. In this study, we found better memory performance in social-dominant mice (Chou et al., 2022). These dominant mice also exhibited greater long-term potentiation and higher memory-related gene expression in the hippocampus, a critical region for memory formation. Daily injection of the memory-improving drug sodium butyrate could also enhance dominance. To validate this correlation across species, through inventory, behavioral and event-related potential studies, we identified better memory abilities in preschool children with higher social dominance. Better memory potentially helped children process dominant facial cues and learn social strategies to acquire higher positions. Our study provides valuable insight into potential implications for preschool education.