A lipid site shapes the agonist response of a pentameric ligand-gated ion channel
We investigated the phospholipid-protein interaction for the bacterial channel, ELIC. Like many neurotransmitter receptors in the brain, ELIC is a protein known as a pentameric ligand-gated ion channel (pLGIC) that responds to the binding of an agonist (such as a drug or neurotransmitter) to conduct ions across the cell membrane. These ion channels are embedded in the lipid bilayer of cells, with lipids affecting how the protein functions in the cell.
The embedded region, the transmembrane domain (TMD), is made up of four conserved alpha helices (M1-M4). The lipid site in this study is formed by a kink in the outermost transmembrane helix, M4, and a conserved triad of protein residues (Trp-Arg-Pro), which directly interact with surrounding membrane lipids. Mutations to the residues in the lipid binding site produced a dynamic M4 helix and accelerated deactivation of the channel, suggesting that bound lipids influence the agonist response.
The embedded region, the transmembrane domain (TMD), is made up of four conserved alpha helices (M1-M4). The lipid site in this study is formed by a kink in the outermost transmembrane helix, M4, and a conserved triad of protein residues (Trp-Arg-Pro), which directly interact with surrounding membrane lipids. Mutations to the residues in the lipid binding site produced a dynamic M4 helix and accelerated deactivation of the channel, suggesting that bound lipids influence the agonist response.
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ELIC is one of the earliest channels to resemble those in the human brain. A lipid binding site on the outer M4 helix is crucial for the agonist to promote activity. A mutation in that binding site reduces activity.
I helped pursue this project in graduate school in hopes of better understanding the evolutionary origins of neurotransmitter receptors that lead to healthy brain functioning. The lipids interacting with these proteins are finally gaining recognition for having a meaningful effect on these receptors, which directly and indirectly influences the brain and brain-related disorders.
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Evolutionary history of pLGICs, most of which reside in the brain.
[1] Camille M. Henault, Cedric Govaerts, Radovan Spurny, Marijke Brams, Argel Estrada-Mondragon, Joseph Lynch, Daniel Bertrand, Els Pardon, Genevieve L. Evans, Kristen Woods, Benjamin W. Elberson, Luis G. Cuello, Grace Brannigan, Hugues Nury, Jan Steyaert, John E. Baenziger, and Chris Ulens. A lipid site shapes the agonist response of a pentameric ligand-gated ion channel. Nature Chemical Biology, October 2019. DOI:10.1038/s41589-019-0369-4
Nicotinic acetylcholine receptor (nAChR) clustering in liquid-disordered domains
This project aimed to characterize the organization of the nicotinic acetylcholine receptors (nAChR): an excitatory neurotransmitter receptor (and pGLIC) that is found in both the brain and muscle tissue. For my research, I focused on the muscle-type nAChR in hopes of understanding neuromuscular disorders. The organization of the nAChRs in the cell membrane is necessary for strong, rapid signaling to the muscle fiber.
I worked on this project for the majority of my MS and PhD studies with a focus on nAChR clustering in respond to large-scale lipid organization surrounding the embedded nAChRs, which is called lipid domain formation.
I worked on this project for the majority of my MS and PhD studies with a focus on nAChR clustering in respond to large-scale lipid organization surrounding the embedded nAChRs, which is called lipid domain formation.
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Structure of the pentameric nAChR found in the muscle cell membrane.
More specifically, we were interested in the interactions between nAChRs and omega-3 fatty acids, which separate from cholesterol and saturated fatty acids to form flexible, liquid-disordered domains.
We found that in domain-forming membranes, nAChRs clustered within liquid-disordered domains, indicating that omega-3 fatty acids may serve as the local lipid environment for nAChR-dimer networks. These findings support the large body of evidence that supports the use of omega-3 fatty acids (through fish and fish/krill oil, for example) in promoting healthy neurological and muscle health.
We found that in domain-forming membranes, nAChRs clustered within liquid-disordered domains, indicating that omega-3 fatty acids may serve as the local lipid environment for nAChR-dimer networks. These findings support the large body of evidence that supports the use of omega-3 fatty acids (through fish and fish/krill oil, for example) in promoting healthy neurological and muscle health.
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The clustering of nAChRs in domain-forming (top) and randomly mixed (bottom) membranes. When lipids have the same tail (homoacid), they organize into DHA (white) vs raft domains. nAChRs cluster within fluid, DHA domains.
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nAChRs and their vast of effects on human neurological and muscle health.
[2] Kristen Woods, Liam Sharp, and Grace Brannigan. Untangling direct and domain-mediated interactions between nicotinic acetylcholine receptors in dha-rich membranes. Journal of Membrane Biology, pages 1,12, July 2019. DOI: 10.1007/s00232-019-00079-0
Understanding self-compassion in relation with body appreciation and gender
Self-compassion is the ability to respond to yourself with the same kindness and understanding that you would give a friend or someone you cared about. Self-compassion and body appreciation are known to be related, but little work has been done to understand their effects on health behaviors separately and together.
We examined the associations of body appreciation and self-compassion with physical activity, sleep, stress management activities, with special attention to gender differences.
We examined the associations of body appreciation and self-compassion with physical activity, sleep, stress management activities, with special attention to gender differences.
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How to practice self-compassion.
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How to practice body appreciation.
We found that self-compassion improved sleep and stress management with negligible gender differences. Additionally, we found that body appreciation improved physical activity and stress management activities more profoundly in women than in men. Body appreciation and self-compassion did not interact in predicting any health behaviors.
Self-compassion and body appreciation are both important for health and well-being, but we found that their effects on specific health behaviors are independent from one another. I studied this topic in hopes of better understanding the practical implication of self-compassion and body appreciation in health psychology.
Self-compassion and body appreciation are both important for health and well-being, but we found that their effects on specific health behaviors are independent from one another. I studied this topic in hopes of better understanding the practical implication of self-compassion and body appreciation in health psychology.
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Why practice self-compassion.
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Body appreciation and its positive effects.
[3] August KJ, Malik D, Markey CH, Woods K, Gerwitz GC. Additive and interactive associations among body appreciation, self-compassion, and gender in understanding college students' health behaviors. Body Image. 2023 Dec;47:101634. DOI: 10.1016/j.bodyim.2023.101634