Modulation of Ligand-Gated Ion Channels as a Novel Pharmacological Principle

Tanasic, Sascha; Rammes, Gerhard; Rupprecht, Rainer

doi:10.1055/s-0031-1271704

Cited by 7 publications

(4 citation statements)

References 32 publications

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“…In addition to co-localization of these drugs with 5-HT 3 receptors, drug concentrations within lipid microdomain fractions correlated highly with their inhibition of serotonin-induced cation currents. This non-competitive antagonism at the 5-HT 3 receptor was not caused by increased receptor internalization, as demonstrated by immunofluorescence, receptor density in clathrin-coated vesicles, and electrophysiology [127]; the antidepressant antagonism of 5-HT 3 also was shown to be independent of the association of 5-HT 3 with lipid microdomains [127,128].…”

Section: -Ht 3 Receptormentioning

confidence: 79%

“…However, the ability of lipid raft co-localizers desipramine and fluoxetine to counter 5-HT 3 effects in N1E-115 cells was not affected by cholesterol depletion [126]. Thus, although lipid rafts have an impact on 5-HT 3 function, antidepressant antagonism of 5-HT 3 appears to be independent of lipid microdomain status [126][127][128].…”

Section: Lipid Microdomains and Antidepressant Treatmentmentioning

confidence: 98%

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Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression

Liu

Hezghia

Shaikh

et al. 2018

Neuropsychopharmacol

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Lipid microdomains ("rafts") are dynamic, nanoscale regions of the plasma membrane enriched in cholesterol and glycosphingolipids, that possess distinctive physicochemical properties including higher order than the surrounding membrane. Lipid microdomain integrity is thought to affect neurotransmitter signaling by regulating membrane-bound protein signaling. Among the proteins potentially affected are monoaminergic receptors and transporters. As dysfunction of monoaminergic neurotransmission is implicated in major depressive disorder and other neuropsychiatric conditions, interactions with lipid microdomains may be of clinical importance. This systematic review evaluates what is known about the molecular relationships of monoamine transporter and receptor regulation to lipid microdomains. The PubMed/MeSH database was searched for original studies published in English through August 2017 concerning relationships between lipid microdomains and serotonin, dopamine and norepinephrine transporters and receptors. Fifty-seven publications were identified and assessed. Strong evidence implicates lipid microdomains in the regulation of serotonin and norepinephrine transporters; serotonin 1A, 2A, 3A, and 7A receptors; and dopamine D1 and β2 adrenergic receptors. Results were conflicting or more complex regarding lipid microdomain associations with the dopamine transporter, D2, D3, and D5 receptors; and negative with respect to β1 adrenergic receptors. Indirect evidence suggests that antidepressants, lipid-lowering drugs, and polyunsaturated fatty acids may exert effects on depression and suicide by altering the lipid milieu, thereby affecting monoaminergic transporter and receptor signaling. The lipid composition of membrane subdomains is involved in localization and trafficking of specific monoaminergic receptors and transporters. Elucidating precise mechanisms whereby lipid microdomains modulate monoamine neurotransmission in clinical contexts can have critical implications for pharmacotherapeutic targeting.

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Section: -Ht 3 Receptormentioning

confidence: 79%

Section: Lipid Microdomains and Antidepressant Treatmentmentioning

confidence: 98%

Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression

Liu

Hezghia

Shaikh

et al. 2018

Neuropsychopharmacol

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“…Among monoaminergic transporters and receptors that are regulated by lipid rafts, we hypothesize that lipid raft alterations would have the greatest impact on suicide risk via effects on serotonin (5-hydroxytryptamine, 5-HT) transporters (SERT) and receptors, given the associations of the serotonergic pathway with suicidal behavior (reviewed in (Mann, 2003, Oquendo, 2014, van Heeringen and Mann, 2014)). Both SERT (Magnani et al, 2004, Samuvel et al, 2005), which regulates synaptic 5-HT concentrations and has effects on the 5-HT receptors, and the 5-HT receptors themselves, most notably the 5-HT 1A (Kalipatnapu and Chattopadhyay, 2005, Kobe et al, 2008, Nothdurfter et al, 2011, Renner et al, 2007, Sjogren et al, 2008), 5-HT 2A (Dreja et al, 2002, Mialet-Perez et al, 2012, Sommer et al, 2009), 5-HT 3A (Eisensamer et al, 2005, Ilegems et al, 2005, Nothdurfter et al, 2010), and 5-HT 7A (Sjogren, 2006, Sjogren and Svenningsson, 2007a, b), localize to lipid rafts.…”

Section: Proposed Model Connecting Cholesterol Reduction With Pufa Stmentioning

confidence: 99%

How lipids may affect risk for suicidal behavior

Daray

Mann

Sublette

2018

Journal of Psychiatric Research

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Suicide and nonfatal suicidal behaviors are major causes of mortality and morbidity worldwide. Variability in rates of suicide and suicidal behaviors within and between countries has been attributed to population and individual risk factors, including economic status and cultural differences, both of which can have suicide risk effects mediated through a variety of factors, of which perhaps the least understood is the role of diet. We therefore review the scientific literature concerning two major dietary lipid classes, cholesterol and polyunsaturated fatty acids (PUFAs), that have been associated with higher risk of suicide attempts and suicide. We consider potential mechanistic intermediates including serotonin transporters and receptors, toll-like receptors (TLRs), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and peroxisome proliferator activated receptors (PPARs). Based on this review, we describe a theoretical model linking cholesterol and PUFA status to suicide risk, taking into account the effects of cholesterol-lowering interventions on PUFA balance, membrane lipid microdomains (rafts) as a nexus of interaction between cholesterol and omega-3 PUFAs, and downstream effects on serotonergic neurotransmission and specific inflammatory pathways.

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“…For example, DHA has robust effects on structural and dynamic characteristics of membrane domains (Huster et al, 1998; Shaikh et al, 2002; Shaikh et al, 2003; Shaikh et al, 2004; Soni et al, 2008; Stillwell et al, 2005b; Turk and Chapkin, 2012; Wassall et al, 2004; Williams et al, 2012) such as domain size and membrane order, likely due to lateral segregation of DHA-rich membrane domains from cholesterol-rich membrane regions. The physiologic implications for neuropsychiatry are profound, since such microdomains participate in regulation of serotonin (Magnani et al, 2004; Samuvel et al, 2005), dopamine (Adkins et al, 2007; Jones et al, 2012), and norepinephrine (Jayanthi et al, 2004; Matthies et al, 2009) transporters; serotonin 1A (Kalipatnapu and Chattopadhyay, 2005; Kobe et al, 2008; Nothdurfter et al, 2011; Pucadyil and Chattopadhyay, 2004; Renner et al, 2007; Sjogren et al, 2008), 2A (Dreja et al, 2002; Mialet-Perez et al, 2012; Sommer et al, 2009), 3A (Eisensamer et al, 2005; Ilegems et al, 2005; Nothdurfter et al, 2010), and 7A (Sjogren et al, 2006; Sjogren and Svenningsson, 2007a; Sjogren and Svenningsson, 2007b) receptors; dopamine uptake (Jones et al, 2012); and dopamine D 2 receptor oligomerization (Celver et al, 2012; Genedani et al, 2005). …”

Section: Polyunsaturated Fatty Acidsmentioning

confidence: 99%

Pathways of polyunsaturated fatty acid utilization: Implications for brain function in neuropsychiatric health and disease

et al. 2015

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Essential polyunsaturated fatty acids (PUFAs) have profound effects on brain development and function. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases such as major depression, bipolar disorder, schizophrenia, Alzheimer’s disease, and attention deficit hyperactivity disorder. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. This article provides an overview of physiologic factors regulating PUFA utilization, highlighting their relevance to neuropsychiatric disease.

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Modulation of Ligand-Gated Ion Channels as a Novel Pharmacological Principle

Abstract: Baseline severity may be only one of many other important clinical variables that mediate clinical outcome, but it is surely an important one deserving further research and consideration.

Cited by 7 publications

References 32 publications

Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression

Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression

How lipids may affect risk for suicidal behavior

Pathways of polyunsaturated fatty acid utilization: Implications for brain function in neuropsychiatric health and disease

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