PI(4,5)P2-dependent and -independent roles of PI4P in the control of hormone secretion by pituitary cells

Abstract

Plasma membrane and organelle membranes are home to seven phosphoinositides, an important class of low-abundance anionic signaling lipids that contribute to cellular functions by recruiting cytoplasmic proteins or interacting with the cytoplasmic domains of membrane proteins. Here, we briefly review the functions of three phosphoinositides, PI4P, PI(4,5)P2, and PI(3,4,5)P3, in cellular signaling and exocytosis, focusing on hormone-producing pituitary cells. PI(4,5)P2, acting as a substrate for phospholipase C, plays a key role in the control of pituitary cell functions, including hormone synthesis and secretion. PI(4,5)P2 also acts as a substrate for class I PI3-kinases, leading to the generation of two intracellular messengers, PI(3,4,5)P3 and PI(3,4)P2, which act through their intracellular effectors, including Akt. PI(4,5)P2 can also influence the release of pituitary hormones acting as an intact lipid to regulate ion channel gating and concomitant calcium signaling, as well as the exocytic pathway. Recent findings also show that PI4P is not only a precursor of PI(4,5)P2, but also a key signaling molecule in many cell types, including pituitary cells, where it controls hormone secretion in a PI(4,5)P2-independent manner.

The Janus-faced functions of Apolipoproteins L in membrane dynamics

“…Apart from Golgi, mitochondrion and lipid droplet membranes, APOLs may also control the dynamics of the plasma membrane. This is suggested by the pleiotropic functions of APOL3-controlled NCS1, which affects surface channels and GPCR activities, exocytosis and synapse formation [33][34][35][36][37][38][39][40]. Moreover, since APOL3 is involved in mitophagosome fusion with endolysosomes, APOL3 could be involved in lysosome membrane dynamics, which is also supported by some PI4KB association with lysosomes [92].…”

“…However, the existence of plasma membrane APOL1 pores remains to be demonstrated, and the surface cationic fluxes were not proven to occur through such pores. Since both NCS1 and the PI4KB product phosphatidylinositol-4-phosphate (PI4P) are involved in cation channel activity at the plasma membrane, including K + efflux by Kv4 channels [33][34][35], delocalizing PI4KB and NCS1 activities from the Golgi as occurs upon APOL3-PI4KB complex disruption [11,16] could affect surface cation fluxes independently of APOL1 pores. In addition, and importantly, the intracellular Ca 2+ fluxes could result not from APOL1 pore activity, but from increased NCS1 binding to GPRCs and GPCR kinases [36][37][38][39] as well as NCS1 binding to IP3Rs, including at endoplasmic reticulum-mitochondrion contact sites (MERCSs) [33,39,40].…”