Biophysical physiology of phosphoinositide rapid dynamics and regulation in living cells

Abstract

Phosphoinositide membrane lipids are ubiquitous low-abundance signaling molecules. They direct many physiological processes that involve ion channels, membrane identification, fusion of membrane vesicles, and vesicular endocytosis. Pools of these lipids are continually broken down and refilled in living cells, and the rates of some of these reactions are strongly accelerated by physiological stimuli. Recent biophysical experiments described here measure and model the kinetics and regulation of these lipid signals in intact cells. Rapid on-line monitoring of phosphoinositide metabolism is made possible by optical tools and electrophysiology. The experiments reviewed here reveal that as for other cellular second messengers, the dynamic turnover and lifetimes of membrane phosphoinositides are measured in seconds, controlling and timing rapid physiological responses, and the signaling is under strong metabolic regulation. The underlying mechanisms of this metabolic regulation remain questions for the future.

Allosteric stabilization of calcium and phosphoinositide dual binding engages several synaptotagmins in fast exocytosis

“…Besides the number of syts, the PI(4,5)P 2 levels also determine how likely it is for syts to engage in dual Ca 2+ /PI(4,5)P 2 binding at an SV (see Figure 3 and Figure 2—figure supplement 7 ). We therefore reasoned that upregulation of PI(4,5)P 2 levels, which are dynamically regulated ( Jensen et al, 2022 ), could potentially compensate for reduced syt expression. To investigate this, we refitted the models with reduced syt levels to the experimental Ca 2+ uncaging data ( Kochubey and Schneggenburger, 2011 ) and only allowed the PI(4,5)P 2 concentration in the slots ([PI(4,5)P 2 ]) to vary.…”

“…As PI(4,5)P 2 levels have a large impact on release kinetics (shown in this study, but also by Walter et al, 2017 ), heterogeneity between RRP SVs might further be enhanced by unequal PI(4,5)P 2 levels. Additionally, the strong impact of PI(4,5)P 2 levels on SV fusion indicates that the dynamic regulation of PI(4,5)P 2 occurring at the seconds time scale might strongly influence synaptic plasticity ( Jensen et al, 2022 ).…”

Molecular architecture of the Gαi-bound TRPC5 ion channel

“…Regarding the ambient PIP 2 concentration in a native plasma membrane, it is generally conceived that physiological [PIP 2 ] is tightly regulated in the midst of a dynamic equilibrium among PIP 2 -synthesizing or degrading enzymes. Even if the equilibrium greatly shifted toward a PIP 2 -degrading direction—such as episodic stimulation of the G q/11 -phospholipase C (PLC) pathway or phosphoinositide 5-phosphatase –, a once deprived [PIP 2 ] would always be replenished within tens of seconds to minutes 51 . That being said, it is highly unlikely to picture a general snapshot of the plasma membrane in which the ambient physiological concentration of PIP 2 is unusually low, probably below a micromolar range.…”

Direct Regulation of the Voltage Sensor of HCN Channels by Membrane Lipid Compartmentalization

“…Membrane lipids play a crucial role in controlling the function of ion channels, acting as key regulators 26,59,60 . However, the significance of compartmentalizing ion channels within lipid domains to regulate their voltage sensing has been largely overlooked, despite its implications for various disease states.…”