Lipid-dependent regulation of ion channels and GPCRs: insights from structures and simulations

Journal article

Ion channels and GPCRs are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP2 plays a key role in regulation of Kv and Kir channels. Likewise, a number of recent cryo-EM structures of TRP channels have revealed bound lipids, including PIP2 and cholesterol. Amongst the pentameric ligand-gated ion channel (pLGIC) family, structural and biophysical studies suggest the M4 TM helix may act as a lipid sensor, e.g. forming part of the binding sites for neurosteroids on the GABAA receptor. Structures of GPCRs have revealed multiple cholesterol sites, which may modulate both receptor dynamics and receptor oligomerization. PIP2 also interacts with GPCRs and may modulate their interactions with G proteins. Overall, it is evident that multiple lipid binding sites exist on channels and receptors which modulate their function allosterically and are potential druggable sites.

Authors: Duncan, A; Song, W; Sansom, MSP

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Annual Reviews
• Journal: Annual Review of Pharmacology and Toxicology
• Volume: 60
• Pages: 31-50
• Publication date: 2019-09-10
• Acceptance date: 2019-04-11
• DOI: 10.1146/annurev-pharmtox-010919-023411
• ISSN: 0362-1642
• Language: English
• Keywords: FFR