Pharmacology of Phosphoinositides, Regulators of Multiple Cellular Functions

Abstract

Inositol phospholipids represent a small fraction of the phospholipids present in all cellular membranes with remarkable importance in regulating various cell functions. They are synthesized from phosphatidylinositol by sequential phosphorylations on the several hydroxyls of the inositol ring to create polyphosphoinositides that function either as docking sites to promote formation of molecular signaling complexes, or serve as precursors for soluble inositol polyphosphates that act as diffusible intracellular messengers. Phosphoinositides are involved in the control of many processes, including membrane traffic, endo- and exocytosis, mitogenesis and apoptosis. Pharmacological tools have helped to clarify many details of phosphoinositide metabolism and have unveiled the roles of these lipids in the control of specific signaling pathways. However, because of their pleiotropic functions it has been questionable whether pharmacological manipulation of inositide formation and metabolism can be of therapeutic value. This review briefly summarizes the means by which inositide functions have been pharmacologically manipulated, and discusses possibilities for specifically targeting certain aspects of their regulatory functions.

Neuronal calcium sensor 1 and phosphatidylinositol 4-OH kinase βinteract in neuronal cells and are translocated to membranes during nucleotide-evoked exocytosis

“…11 1985), secretory granules (Wiedemann et al, 1996), synaptic vesicles (Wiedemann et al, 1998), Golgi (Jergil and Sundler, 1983;Cockcroft et al, 1985) and glucose transporter 4-containing transport vesicles (Del Vecchio and Pilch, 1991), little is known about the subcellular localization of PI4K proteins in neurons and neuroendocrine cells (Balla et al, 2000). Different types of PI4Ks have been cloned and characterized from yeast and mammalian cells (Balla, 1998;Fruman et al, 1998;Nakagawa et al, 1996a;Nakagawa et al, 1996b;Meyers and Cantley, 1997) and it is clear from these studies that different isoforms of the PI4K family may synthesize different pools of polyphosphoinositides that in turn modulate different cellular functions (De Camilli et al, 1996;Anderson et al, 1999;Balla, 2001;Cremona and DeCamilli, 2001). The localization of distinct kinase isoforms to specific sites in cellular compartments helps to explain the different roles that phosphoinositides play in cells.…”

Dual Regulation of TRPV1 by Phosphoinositides

“…In our hands, even in this protocol U73122 induced a small decrease in the FRET signal. This could be attributable to the reported variability between U73122 batches (Balla, 2001). More importantly, capsaicin applied after pretreatment with U73122 induced only a negligible PtdIns(4,5)P 2 hydrolysis (Fig.…”

Continuous phosphatidylinositol metabolism is required for cleavage of crane fly spermatocytes

“…However, regression of U7-treated furrows in crane fly spermatocytes appeared much more rapid than in fwd mutants (R. Wong and J.A.B., unpublished). Because U7 has been reported to interfere with the in vivo activity of multiple isoforms of PLC (Balla, 2001), the rapid effect of this drug on cleavage stability suggests that PtdIns(4,5)P2 hydrolysis and perhaps the downstream products, DAG, Ins(1,4,5)P3 and calcium, are continuously required for maintaining the cleavage furrow and for continuing ingression. Our results are compatible with a role for calcium in cleavage in this system, but direct measurements of calcium in drug-treated and untreated crane fly spermatocytes would be needed to address this directly.…”