PHOSPHOINOSITIDES AND CALCIUM SIGNALING. A MARRIAGE ARRANGED IN ER-PM CONTACT SITES

Abstract

Calcium (Ca²⁺) ions are critically important in orchestrating countless regulatory processes in eukaryotic cells. Consequently, cells tightly control cytoplasmic Ca²⁺ concentrations using a complex array of Ca²⁺-selective ion channels, transporters, and signaling effectors. Ca²⁺ transport through various cellular membranes is highly dependent on the intrinsic properties of specific membrane compartments and conversely, local Ca²⁺ changes have profound effects on the membrane lipid composition of such membrane sub-domains. In particular, inositol phospholipids are a minor class of phospholipids that play pivotal roles in the control of Ca²⁺-dependent signaling pathways. In this review, we will highlight some of the recent advances in this field as well as their impact in defining future research directions.

Keywords: Ca2+ channels; Phosphatidylinositol; calcium; membrane contact sites; phosphatidylinositol 4-kinase.

Figure 1. Interrelationship between Ca²⁺ influx and non-vesicular lipid transport in ER-PM contact sites

(A) Store operated Ca²⁺ entry is triggered by the concerted communication between the ER-localized STIM1 and PM-localized Orai1 proteins in ER-PM contact sites. The polybasic domains (PBD) of STIM1 is kept at the PM by interaction with phosphoinositides PI4P and PI(4,5)P₂. Several proteins involved in non-vesicular lipid transport are also located in ER-PM contact sites. Many of these proteins are regulated by Ca²⁺ either directly or via phospholipase C (PLC)-mediated changes in phosphoinositides. Extended synaptotagmins (E-Syt1/2/3) maintain contacts with the PM through their C2 domains and are anchored to the ER by an N-terminal membrane anchoring hook. They also contain SMP domains that can form lipid tunnels and can transport diacylglycerol (DAG). The oxysterol binding protein related ORP5 and ORP8 are anchored to the ER via a C-terminal transmembrane domain and interact with the PM phosphoinositides through their N-terminal sequences containing a pleckstrin homology (PH) domain. These proteins consume the PI4P gradient between the two membranes to transport phosphatidylserine (PS) from the ER to the PM. GRAMD1/Aster proteins are fixed in the ER by their N-terminal membrane spanning domain and interact with the membrane by a GRAM domain. This interaction is facilitated by PM cholesterol. The VASt domains of these proteins transfer cholesterol from the PM to the ER. The PI transfer proteins, Nir2 and Nir3 interact with the ER through interaction with the ER-localized VAPA/B proteins and bind to the PM when DAG and PA are produced during receptor activation. Their N-terminal lipid transfer domains transfers PA from the PM to the ER and most likely also delivers PI in the opposite direction. Important lipid transfer proteins, such as TMEM24 or ORP3, both regulated by Ca²⁺ and protein kinase C (PKC) are omitted for clarity. See text for discussion of these proteins. (B) Schematic diagram depicting the connection between Ca²⁺ signals and the various proteins that work in ER-PM contact sites. Local or global cytoplasmic Ca²⁺ increasesdi rectly activate enzymes such as PLC or PKC isoforms or the PS scramblase TMEMF16F or E-Syt1. As a result, several lipids are changing in the PM, possibly confined to contact sites if the Ca²⁺ signal is limited. Those lipid changes, in turn, affect the lipid transport proteins, primarily by controlling their PM association, leading to secondary changes in lipids in these membrane compartments. Such lipid changes then affect Ca²⁺ channels including SOCE. Color codes: Rectangles filled red are enzymes controlled by Ca²⁺. Rounded rectangles filled light yellow are lipids. Phosphoinositides are labeled with red. Rounded rectangles filled light green, are non-vesicular lipid transfer proteins. GRAMD2 does not have a lipid transfer domain, therefore, it is lighter colored in a rectangle. Rounded rectangles filled light blue are multi transmembrane proteins with flippase or scramblase function. Dark blue ovals are channels capable of Ca²⁺ transport.