Altered Membrane Mechanics Provides a Receptor‐Independent Pathway for Serotonin Action

Abstract

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.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Tryptophan [376][377][378], Glycine [139,284], Glutamate [139], Aginine [379], Alanine [379], 5-aminolevulinic acid and its esters [380], L-dopa [138,199,381,382] Nucleotides ATP [383], UMP [384], DNA [385], ADOMET [381] Sugars and carbohydrates Trehalose [386], Gastrodin [387], Mannitol [199], 1,3,7-trimethyluric acid [388] Neurotransmitters Dopamine [138,[389][390][391][392][393][394][395][396][397], Serotonin [138,378,389,396,[398][399][400][401][402], Adenosine [138], Melatonin [138,229,378,389,[403][404]…”

Antidepressants stimulate lipoprotein(a) macropinocytosis via serotonin-enhanced cell surface binding

“…HepG2 cells only express minimal levels of the serotonin receptors 1A and 1D and the highest level of the serotonin transporter of any human cell line (Human Protein Atlas 48 ). Imipramine and citalopram treatment may enhance Lp(a) surface binding by inhibiting the serotonin transporter, allowing accumulation of extracellular serotonin and inducing membrane changes as observed by Dey et al 47 .…”

“…Serotonin transporter inhibition prevents serotonin uptake from the extracellular space 46 , leading to elevated extracellular serotonin levels. Interestingly, a recent study found addition of exogenous serotonin to cells enhances transferrin cell surface binding and subsequent endocytosis by altering the physical properties of the plasma membrane independent of serotonin receptors or transporter 47 . HepG2 cells only express minimal levels of the serotonin receptors 1A and 1D and the highest level of the serotonin transporter of any human cell line (Human Protein Atlas 48 ).…”

“…Plasma serotonin levels are often decreased in patients with depression 67–69 . Serotonin has been recently discovered to be a regulator of cargo binding to the plasma membrane 47 . Consistent with this, we found that serotonin increased plasma membrane binding of Lp(a) to the cell surface, and this enhanced binding subsequently increased Lp(a) uptake by macropinocytosis.…”

Selective Advantages of Synapses in Evolution

“…Small transmitters directly interact with membranes and can be broadly divided into two groups. Lipophilic transmitters (i.e., melatonin, serotonin, histamine, dopamine, noradrenaline, adrenaline, and adenosine) had high lipid partition coefficients (Wang et al, 2011 ; Postila et al, 2016 ; Engberg et al, 2020 ; Josey et al, 2020 ; Parkkila and Viitala, 2020 ) and can operate in receptor-independent mechanisms by changing lipid dynamics (Dey et al, 2021 ). They accumulated within surface membrane layers (e.g., postsynaptic membranes) with enhanced planar 2D diffusions.…”