Dataset Information

Assessing Panic: Bridging the Gap Between Fundamental Mechanisms and Daily Life Experience.

ABSTRACT: Panic disorder (PD) is one of the most common psychiatric disorders. Recurrent, unexpected panic attacks (PAs) are the primary symptom and strongly impact patients' quality of life. Clinical manifestations are very heterogeneous between patients, emphasizing the need for a dimensional classification integrating various aspects of neurobiological and psychological circuits in line with the Research Domain Criteria (RDoC) proposed by the US National Institute of Mental Health. To go beyond data that can be collected in the daily clinical situation, experimental panic provocation is widely used, which has led to important insights into involved brain regions and systems. Genetic variants can determine the sensitivity to experimental models such as carbon dioxide (CO2) exposure and can increase the risk to develop PD. Recent developments now allow to better assess the dynamic course of PAs outside the laboratory in patients' natural environment. This can provide novel insights into the underlying mechanisms and the influence of environmental factors that can alter gene regulation by changing DNA methylation. In this mini review, we discuss assessment of PAs in the clinic, in the laboratory using CO2 exposure, genetic associations, and the benefits of real-life assessment and epigenetic research.

SUBMITTER: Leibold NK

PROVIDER: S-EPMC6232935 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Assessing Panic: Bridging the Gap Between Fundamental Mechanisms and Daily Life Experience.

Leibold Nicole K NK Schruers Koen R KR

Frontiers in neuroscience 20181024

Panic disorder (PD) is one of the most common psychiatric disorders. Recurrent, unexpected panic attacks (PAs) are the primary symptom and strongly impact patients' quality of life. Clinical manifestations are very heterogeneous between patients, emphasizing the need for a dimensional classification integrating various aspects of neurobiological and psychological circuits in line with the Research Domain Criteria (RDoC) proposed by the US National Institute of Mental Health. To go beyond data th ...[more]

PMID: 30459546

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Project description:The Na(+)-glucose cotransporter hSGLT1 is a member of a class of membrane proteins that harness Na(+) electrochemical gradients to drive uphill solute transport. Although hSGLT1 belongs to one gene family (SLC5), recent structural studies of bacterial Na(+) cotransporters have shown that Na(+) transporters in different gene families have the same structural fold. We have constructed homology models of hSGLT1 in two conformations, the inward-facing occluded (based on vSGLT) and the outward open conformations (based on Mhp1), mutated in turn each of the conserved gates and ligand binding residues, expressed the SGLT1 mutants in Xenopus oocytes, and determined the functional consequences using biophysical and biochemical assays. The results establish that mutating the ligand binding residues produces profound changes in the ligand affinity (the half-saturation concentration, K(0.5)); e.g., mutating sugar binding residues increases the glucose K(0.5) by up to three orders of magnitude. Mutation of the external gate residues increases the Na(+) to sugar transport stoichiometry, demonstrating that these residues are critical for efficient cotransport. The changes in phlorizin inhibition constant (K(i)) are proportional to the changes in sugar K(0.5), except in the case of F101C, where phlorizin K(i) increases by orders of magnitude without a change in glucose K(0.5). We conclude that glucose and phlorizin occupy the same binding site and that F101 is involved in binding to the phloretin group of the inhibitor. Substituted-cysteine accessibility methods show that the cysteine residues at the position of the gates and sugar binding site are largely accessible only to external hydrophilic methanethiosulfonate reagents in the presence of external Na(+), demonstrating that the external sugar (and phlorizin) binding vestibule is opened by the presence of external Na(+) and closes after the binding of sugar and phlorizin. Overall, the present results provide a bridge between kinetics and structural studies of cotransporters.

Dataset Information

Assessing Panic: Bridging the Gap Between Fundamental Mechanisms and Daily Life Experience.

Publications

Assessing Panic: Bridging the Gap Between Fundamental Mechanisms and Daily Life Experience.

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