Phosphoinositides regulate ion channels

Abstract

Phosphoinositides serve as signature motifs for different cellular membranes and often are required for the function of membrane proteins. Here, we summarize clear evidence supporting the concept that many ion channels are regulated by membrane phosphoinositides. We describe tools used to test their dependence on phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate, and consider mechanisms and biological meanings of phosphoinositide regulation of ion channels. This lipid regulation can underlie changes of channel activity and electrical excitability in response to receptors. Since different intracellular membranes have different lipid compositions, the activity of ion channels still in transit towards their final destination membrane may be suppressed until they reach an optimal lipid environment.

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

“…To date, there is clear evidence supporting the regulating role of phosphoinositides in the activity of many ion channels (Hille et al, 2015). Fan and Makielski (1997) showed for the first time that the K ATP channels are regulated by the phosphatidylinositol 4-5 biphosphate (PIP2).…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Membrane Phospholipids. Various G proteincoupled receptors (GPCRs) (e.g., muscarinic acetylcholine receptors) can inhibit voltage-gated calcium channels, including LTCCs (Suh and Hille, 2005;Hille et al, 2015), through activation of phospholipase C. Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) seems to stabilize active channel conformations by tethering cytoplasmic domains, bound to its inositol phosphates, to the plasma membrane to which PIP 2 is anchored through its fatty acid side chains (Suh et al, 2012). This can explain the reduction of Ca 2+ channel currents by receptor-mediated PIP 2 depletion.…”

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

“…Phosphatidylinositol(4,5)bisphosphate (PIP 2 ) is a minor (<1%) acidic phospholipid found in the inner leaflet of the cell membrane and plays a vital part in cellular signaling by directly interacting with membrane proteins, including Kv7 potassium channels (Gamper and Shapiro, 2007;Suh and Hille, 2008;Hille et al, 2014;Zaydman and Cui, 2014). Function of Kv7 channels is absolutely dependent on PIP 2 (Zaydman and Cui, 2014) and activation of phospholipase C, and subsequent PIP 2 hydrolysis causes downregulation of their activity, which in turn lowers the threshold for activity (Brown et al, 2007), orchestrating excitability in brain, heart, skeletal muscle and inner ear.…”