Search for: All records

Type A γ-aminobutyric acid receptors (GABA_ARs) are inhibitory pentameric ligand-gated ion channels in the brain. Many anesthetics and neurosteroids act through binding to the GABA_AR transmembrane domain (TMD), but the structural basis of their actions is not well understood and no resting-state GABA_AR structure has been determined. Here, we report crystal structures of apo and the neurosteroid anesthetic alphaxalone-bound desensitized chimeric α1GABA_AR (ELIC-α1GABA_AR). The chimera retains the functional and pharmacological properties of GABA_ARs, including potentiation, activation and desensitization by alphaxalone. The apo-state structure reveals an unconventional activation gate at the intracellular end of the pore. The desensitized structure illustrates molecular determinants for alphaxalone binding to an inter-subunit TMD site. These structures suggest a plausible signaling pathway from alphaxalone binding at the bottom of the TMD to the channel gate in the pore-lining TM2 through the TM1–TM2 linker. The study provides a framework to discover new GABA_AR modulators with therapeutic potential.

Obesity is a serious health issue affecting humanity on a global scale. Recognized by the American Medical Association as a chronic disease, the incidence of obesity continues to grow at an accelerating rate and obesity has become one of the major threats to human health. Excessive weight gain is tied to metabolic syndrome, which is shown to increase the risk of chronic diseases, such as heart disease and type 2 diabetes, taxing an already overburdened healthcare system and increasing mortality worldwide. Available treatments such as bariatric surgery and pharmacotherapy are often accompanied by adverse side effects and poor patient compliance. Nanotechnology, an emerging technology with a wide range of biomedical applications, has provided an unprecedented opportunity to improve the treatment of many diseases, including obesity. This review provides an introduction to obesity and obesity‐related comorbidities. The most recent developments of nanotechnology‐based drug delivery strategies are highlighted and discussed. Additionally, challenges and consideration for the development of nanoformulations with translational potential are discussed. The overall objective of this review is to enhance the understanding of the design and development of nanomedicine for treatments of obesity and related comorbidities.