Serotonin, an importants ignalingm olecule in humans, has an unexpectedly high lipid membrane affinity. The significance of this finding has evokedc onsiderable speculation. Here we show that membrane binding by serotonin can directly modulate membrane properties and cellular function, providing an activity pathway completelyi ndependent of serotonin receptors. Atomic force microscopy shows that serotonin makes artificial lipid bilayers softer,a nd inducesn ucleation of liquid disordered domains inside the raft-likel iquid-ordered domains. Solid-state NMR spectrosco-py corroborates this data at the atomic level,r evealing ah omogeneous decrease in the order parameter of the lipid chainsi nt he presence of serotonin. In the RN46A immortalized serotonergicn euronal cell line, extracellular serotonin enhances transferrin receptor endocytosis, even in the presence of broad-spectrum serotonin receptor and transporter inhibitors. Similarly,i ti ncreases the membrane binding and internalizationo fo ligomeric peptides. Our resultsu ncover a mode of serotonin-membrane interaction that can potentiate key cellular processes in ar eceptor-independent fashion.

While the roles of intrinsically disordered protein domains in driving many interactions are increasingly well‐appreciated, the mechanism of toxicity of disease‐causing disordered proteins remains poorly understood. A prime example is Alzheimer's disease (AD) associated amyloid beta (Aβ). Aβ oligomers are highly toxic partially structured peptide assemblies with a distinct ordered region (residues ~10–40) and a shorter disordered region (residues ~1–9). Here, we investigate the role of this disordered domain and its relation to the ordered domain in the manifestation of toxicity through a set of Aβ fragments and stereo‐isomers designed for this purpose. We have measured their effects on lipid membranes and cultured neurons, probing their toxicity, intracellular distributions, and specific molecular interactions using the techniques of confocal imaging, lattice light sheet imaging, fluorescence lifetime imaging, and fluorescence correlation spectroscopy (FCS). Remarkably, we find that neither part ‐ Aβ10–40 or Aβ1–9, is toxic by itself. The ordered part (Aβ10–40) is the major determinant of how Aβ attaches to lipid bilayers, enters neuronal cells, and localizes primarily in the late endosomal compartments. However, once Aβ enters the cell, it is the disordered part (only when it is connected to the rest of the peptide) which has a strong and stereospecific interaction with an unknown cellular component, as demonstrated by distinct changes in the fluorescence lifetime of a fluorophore attached to the N‐terminal. This interaction appears to commit Aβ to the toxic pathway. Our findings correlate well with Aβ sites of familial AD mutations, a significant fraction of which cluster in the disordered region. We conclude that while the ordered region dictates attachment and cellular entry, the key to toxicity lies in the ordered part presenting the disordered part for a specific cellular interaction. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Single molecule imaging addresses the “which oligomer” question in membrane mediated toxicity of amyloid oligomers.

AbstractSerotonin is a neurotransmitter as well as a somatic signaling molecule, and the serotonergic system is a major target for psychotropic drugs. Serotonin, together with a few related neurotransmitters, has recently been found to exhibit an unexpectedly high lipid membrane affinity1–3. It has been conjectured that extrasynaptic serotonin can diffuse in the lipid membrane to efficiently reach remote receptors (and receptors with buried ligand-binding sites)4, providing a mechanism for the diffuse ‘volume’ neurotransmission that serotonin is capable of5–10. Here we show that membrane binding by serotonin can directly modulate membrane properties and cellular function, independent of its receptor-mediated actions. Atomic force microscopy shows that serotonin binding makes artificial lipid bilayers softer. It induces nucleation of liquid disordered domains inside the raft-like liquid-ordered domains in a ternary bilayer displaying phase separation. Solid-state NMR spectroscopy corroborates this data, revealing a rather homogeneous decrease in the order parameter of the lipid chains in the presence of serotonin. In the RN46A immortalized serotonergic neuronal cell line, extracellular serotonin enhances transferrin receptor endocytosis, an action exerted even in the presence of both broad-spectrum serotonin receptor and transporter inhibitors. Similarly, it increases the binding and internalization of Islet Amyloid Polypeptide (IAPP) oligomers, suggesting a connection between serotonin, which is co-secreted with IAPP by pancreatic beta cells, and the cellular effects of IAPP. Our results uncover a hitherto unknown serotonin-bilayer interaction that can potentiate key cellular processes in a receptor-independent fashion. Therefore, some pathways of serotonergic action may escape potent pharmaceutical agents designed for serotonin transporters or receptors. Conversely, bio-orthogonal serotonin-mimetics may provide a new class of cell-membrane modulators.

Hydatid cyst may be found in almost any part of the body, but most often in the liver and the lungs. Other organs affected occasionally include the brain, muscle, kidney, heart, pancreas, adrenal, and thyroid gland. Hydatidosis located in the thyroid is an infrequent finding, even in endemic regions. This report documents a rare case with a cystic nodule in the thyroid detected by ultrasonography. The patient was a 30-year-old woman with an euthyroid multinodular goitre. Ultrasonography revealed a cystic nodule, and the ultrasonic appearance of the cyst liquid showed multiple echoes, suggesting that the nodule could be a hydatid cyst. The histopathologic examinations confirmed this to be a primary hydatid cyst of thyroid. During the differential diagnosis of the cystic thyroid lesions, hydatid disease of the thyroid gland should be considered in endemic areas. Chemotherapy is necessary to avoid recurrence. DOI: http://dx.doi.org/10.3126/ajms.v5i2.8830 Asian Journal of Medical Science, Volume-5(2) 2014: 143-145