Lipid agonism: The PIP2 paradigm of ligand-gated ion channels

Abstract

The past decade, membrane signaling lipids emerged as major regulators of ion channel function. However, the molecular nature of lipid binding to ion channels remained poorly described due to a lack of structural information and assays to quantify and measure lipid binding in a membrane. How does a lipid-ligand bind to a membrane protein in the plasma membrane and what does it mean for a lipid to activate or regulate an ion channel? How does lipid-binding compare to activation by soluble neurotransmitter? And how does the cell control lipid agonism? This review focuses on lipids and their interactions with membrane proteins, in particular ion channels. I discuss the intersection of membrane lipid biology and ion channel biophysics. A picture emerges of membrane lipids as bona fide agonists of ligand-gated ion channels. These freely diffusing signals reside in the plasma membrane, bind to the transmembrane domain of protein, and cause a conformational change that allosterically gates an ion channel. The system employs a catalog of diverse signaling lipids ultimately controlled by lipid enzymes and raft localization. I draw upon pharmacology, recent protein structure, and electrophysiological data to understand lipid regulation and define inward rectifying potassium channels (Kir) as a new class of PIP2 lipid-gated ion channels.

Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D

“…3). Labelling artefacts from PIP 2 antibodies are unlikely, as PIP 2 is polyunsaturated and expected to reside in the liquid disordered region of the membrane20.…”

“…22) could localize PLD to cholesterol rich rafts24 away from its substrate PC (refs 20, 25). Furthermore, PIP 2 activates PLD (ref.…”

Lipids as central modulators of sensory TRP channels

“…Interestingly, the relative abundance of diet-derived fatty acids may affect the phospholipid composition of the membrane and potentially influence the acyl composition of PIP 2 [144]. In addition, lipid rafts modulation through depletion of their components or dietary intake of PUFAs may perturb PIP 2 signaling [145;146].…”

Ryanodine and IP3 receptor-mediated calcium signaling play a pivotal role in neurological infrared laser modulation

“…IR rapid heating/cooling of water also creates capacitive photothermal currents, which results in plasma membrane depolarization/repolarization 19 and thus possible activation of the voltage sensitive phosphatase (Ci-VSP). Recently, Ci-VSP was shown to regulate PIP 2 signaling in the plasma membrane [64][65][66] and could be accounted for the initial depletion during IR-induced cellular response.…”