Conn's: Current Thrapy 2005, 56\ub0 Edizione

Covering more than 300 clinically relevant topics, Conn's Current Therapy offers an in-depth, personal approach to treatment from international experts, ideally suited for today's busy medical practitioners

Data_Sheet_1_Analyzing the mechanisms that facilitate the subtype-specific assembly of γ-aminobutyric acid type A receptors.DOCX

Impaired inhibitory signaling underlies the pathophysiology of many neuropsychiatric and neurodevelopmental disorders including autism spectrum disorders and epilepsy. Neuronal inhibition is regulated by synaptic and extrasynaptic γ-aminobutyric acid type A receptors (GABAARs), which mediate phasic and tonic inhibition, respectively. These two GABAAR subtypes differ in their function, ligand sensitivity, and physiological properties. Importantly, they contain different α subunit isoforms: synaptic GABAARs contain the α1–3 subunits whereas extrasynaptic GABAARs contain the α4–6 subunits. While the subunit composition is critical for the distinct roles of synaptic and extrasynaptic GABAAR subtypes in inhibition, the molecular mechanism of the subtype-specific assembly has not been elucidated. To address this issue, we purified endogenous α1- and α4-containing GABAARs from adult murine forebrains and examined their subunit composition and interacting proteins using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and quantitative analysis. We found that the α1 and α4 subunits form separate populations of GABAARs and interact with distinct sets of binding proteins. We also discovered that the β3 subunit, which co-purifies with both the α1 and α4 subunits, has different levels of phosphorylation on serines 408 and 409 (S408/9) between the two receptor subtypes. To understand the role S408/9 plays in the assembly of α1- and α4-containing GABAARs, we examined the effects of S408/9A (alanine) knock-in mutation on the subunit composition of the two receptor subtypes using LC-MS/MS and quantitative analysis. We discovered that the S408/9A mutation results in the formation of novel α1α4-containing GABAARs. Moreover, in S408/9A mutants, the plasma membrane expression of the α4 subunit is increased whereas its retention in the endoplasmic reticulum is reduced. These findings suggest that S408/9 play a critical role in determining the subtype-specific assembly of GABAARs, and thus the efficacy of neuronal inhibition.</p

Image_2_Analyzing the mechanisms that facilitate the subtype-specific assembly of γ-aminobutyric acid type A receptors.JPEG

Impaired inhibitory signaling underlies the pathophysiology of many neuropsychiatric and neurodevelopmental disorders including autism spectrum disorders and epilepsy. Neuronal inhibition is regulated by synaptic and extrasynaptic γ-aminobutyric acid type A receptors (GABAARs), which mediate phasic and tonic inhibition, respectively. These two GABAAR subtypes differ in their function, ligand sensitivity, and physiological properties. Importantly, they contain different α subunit isoforms: synaptic GABAARs contain the α1–3 subunits whereas extrasynaptic GABAARs contain the α4–6 subunits. While the subunit composition is critical for the distinct roles of synaptic and extrasynaptic GABAAR subtypes in inhibition, the molecular mechanism of the subtype-specific assembly has not been elucidated. To address this issue, we purified endogenous α1- and α4-containing GABAARs from adult murine forebrains and examined their subunit composition and interacting proteins using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and quantitative analysis. We found that the α1 and α4 subunits form separate populations of GABAARs and interact with distinct sets of binding proteins. We also discovered that the β3 subunit, which co-purifies with both the α1 and α4 subunits, has different levels of phosphorylation on serines 408 and 409 (S408/9) between the two receptor subtypes. To understand the role S408/9 plays in the assembly of α1- and α4-containing GABAARs, we examined the effects of S408/9A (alanine) knock-in mutation on the subunit composition of the two receptor subtypes using LC-MS/MS and quantitative analysis. We discovered that the S408/9A mutation results in the formation of novel α1α4-containing GABAARs. Moreover, in S408/9A mutants, the plasma membrane expression of the α4 subunit is increased whereas its retention in the endoplasmic reticulum is reduced. These findings suggest that S408/9 play a critical role in determining the subtype-specific assembly of GABAARs, and thus the efficacy of neuronal inhibition.</p

Ten questions concerning the implications of carpet on indoor chemistry and microbiology

Carpet and rugs currently represent about half of the United States flooring market and offer many benefits as a flooring type. How carpets influence our exposure to both microorganisms and chemicals in indoor environments has important health implications but is not well understood. The goal of this manuscript is to consolidate what is known about how carpet impacts indoor chemistry and microbiology, as well as to identify the important research gaps that remain. After describing the current use of carpet indoors, questions focus on five specific areas: 1) indoor chemistry, 2) indoor microbiology, 3) resuspension and exposure, 4) current practices and future needs, and 5) sustainability. Overall, it is clear that carpet can influence our exposures to particles and volatile compounds in the indoor environment by acting as a direct source, as a reservoir of environmental contaminants, and as a surface supporting chemical and biological transformations. However, the health implications of these processes are not well known, nor how cleaning practices could be optimized to minimize potential negative impacts. Current standards and recommendations focus largely on carpets as a primary source of chemicals and on limiting moisture that would support microbial growth. Future research should consider enhancing knowledge related to the impact of carpet in the indoor environment and how we might improve the design and maintenance of this common material to reduce our exposure to harmful contaminants while retaining the benefits to consumers.Both the workshop and the development of this manuscript were supported by the Alfred P. Sloan Foundation, grant G-2018-11240