A Novel CCK Receptor GPR173 Mediates Potentiation of GABAergic Inhibition.

Cholecystokinin (CCK) enables excitatory circuit long-term potentiation (LTP). Here, we investigated its involvement in the enhancement of inhibitory synapses. Activation of GABA neurons suppressed neuronal responses in the neocortex to a forthcoming auditory stimulus in mice of both sexes. High-frequency laser stimulation (HFLS) of GABAergic neurons potentiated this suppression. HFLS of CCK interneurons could induce the LTP of their inhibition toward pyramidal neurons. This potentiation was abolished in CCK knock-out mice but intact in mice with both CCK1R and 2R knockout of both sexes. Next, we combined bioinformatics analysis, multiple unbiased cell-based assays, and histology examinations to identify a novel CCK receptor, GPR173. We propose GPR173 as CCK3R, which mediates the relationship between cortical CCK interneuron signaling and inhibitory LTP in the mice of either sex. Thus, GPR173 might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.SIGNIFICANCE STATEMENT CCK, the most abundant and widely distributed neuropeptide in the CNS, colocalizes with many neurotransmitters and modulators. GABA is one of the important inhibitory neurotransmitters, and much evidence shows that CCK may be involved in modulating GABA signaling in many brain areas. However, the role of CCK-GABA neurons in the cortical microcircuits is still unclear. We identified a novel CCK receptor, GPR173, localized in the CCK-GABA synapses and mediated the enhancement of the GABA inhibition effect, which might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.

Correlated Motions and Dynamics in Different Domains of Epidermal Growth Factor Receptor With L858R and T790M Mutations.

Non-small cell lung cancer with an activating epidermal growth factor receptor (EGFR) mutation responds well to targeted drugs. In most cases, drug resistance appears after about a year. Several studies have been conducted on the kinase domain of EGFR to understand the drug resistance mechanism. Since EGFR is a multi-domain protein, mutation in the kinase domain may affect the other domains as well. In this study, we examine the complete structure of the multi-domain EGFR protein and its mutants. We performed molecular dynamics simulations for wildtype EGFR, EGFR with L858R mutation, and EGFR with L858R and T790M mutations. We applied normal mode analysis and complex network analysis to extract the correlated motions in the domains of EGFR. The normal modes are used to construct the dynamic cross-correlation map (DCCM). Simulation results show different patterns of correlated motions in each domain of EGFR mutants compared to the wildtype. In Domains 1 and 3 of the extracellular region, a small number of weak positively correlated motions are extracted. Domains 2 and 4 show large numbers of both positive and negative motions. However, the negatively correlated motions are stronger in mutant structures compared to the wildtype. In Domain 7, some residues showed a positive correlation around the main diagonal. We also identified different communities, nodes and crucial residues in the domains of the structures, which can be important for the function of EGFR. Moreover, hydrogen bond analysis is performed for the stability analysis. The mutant structures have fewer hydrogen bonds compared to the wildtype. Overall, these findings are useful for understanding the dynamics and communications in EGFR domains.

Hydrogen bond analysis of the EGFR-ErbB3 heterodimer related to non-small cell lung cancer and drug resistance.

Lung cancer is the predominant cause of cancer deaths on a worldwide scale. A mutation in the epidermal growth factor receptor (EGFR) can cause non-small cell lung cancer (NSCLC). The L858R one-point mutation in exon 21 in EGFR is the most prevalent in NSCLC. For over 60% of EGFR-muted NSCLC, another mutation T790M can cause drug resistance. In this paper, we consider EGFR and ErbB3 heterodimers involving three structures of EGFR, wild-type, with L858R mutation, and with L858R and T790M mutations. We perform molecular dynamics (MD) simulations to analyze hydrogen bonds in all three instances. The hydrogen bonds contribute to the conformational stability of the protein and molecular recognition. Several other parameters are also investigated in the present study, which reveals significant changes in the dimer at different levels of mutation. The knowledge and results obtained from this study lead to useful insight into the mechanism of NSCLC drug resistance.