Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Published: February 2024
AI Article Synopsis
Article Abstract
The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here we report a 3.1 Å resolution cryo-EM structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.
We aimed to examine the relationship of Dopamine transporter (DAT) and vesicular monoamine transporter (VMAT-2) gene and protein levels with psychic experiences and other clinical parameters in individuals with Methamphetamine Use Disorder (MUD). This study included 50 males diagnosed with MUD and 50 males as a smoking control (SC) and nonsmoking control (NSC). Community Assessment of Psychic Experiences (CAPE) was administered to patients and controls; Addiction Profile Index, Treatment Motivation Questionnaire, and Substance Craving Scale were administered only to the patient group.
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA.
In recent years, methamphetamine (METH) misuse in the US has been rapidly increasing, and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including the dysfunction of the neuroprotective protein parkin.
Serotonin (5-HT), a versatile signaling molecule, plays a variety of roles in both neurotransmission and tissue regulation. The influence of serotonin on early development was first studied in marine invertebrate embryos and has since been documented in a variety of vertebrate species, including mammals. The present study investigates the expression and functional activity of serotonin components in mouse embryos, focusing on key receptors and transporters.
Parkinson's disease is a pathology with a wide range of and models available. Among these, the SH-SY5Y neuroblastoma cell line is one of the most employed. This model expresses catecholaminergic markers and can differentiate and acquire various neuronal phenotypes.
Neurons deploy diverse adaptive strategies to ensure survival and neurotransmission amid cellular stress. When these adaptive pathways are overwhelmed, functional impairment or neurodegeneration follows. Here we show that stressed neurons actively induce a state of transmissive dormancy as a protective measure.
