Phosphatidylinositol in Transmembrane Signaling

Inositol trisphosphate opens a calcium transport channel in the membrane of the endoplasmic reticulum. This leads to an influx of calcium from storage in the endoplasmic reticulum and a 10-fold increase in the cytosolic concentration of calcium ions. Calmodulin is a small calcium binding protein found in all cells. Its affinity for calcium is such that, at the resting concentration of calcium in the cytosol (of the order of 0.1 /xmol per L), little or none is bound to calmodulin. When the cytosolic concentration of calcium rises to about 1 /xmol per L, as occurs in response to opening of the endoplasmic reticulum calcium transport channel, calmodulin binds 4 mol of calcium per mol of protein. When this occurs, calmodulin undergoes a conformational change, and calcium-calmodulin binds to, and activates, cytosolic protein kinases, which in turn phosphorylate target enzymes. 

The diacylglycerol released by phospholipase C action remains in the membrane, where it activates a membrane-bound protein kinase. It may also diffuse into cytosol, where it enhances the binding of calcium-calmodulin to cytosolic protein kinase. 

Inositol trisphosphate is inactivated by further phosphorylation to inositol tetrakisphosphate, and diacylglycerol is inactivated by hydrolysis to glycerol and fatty acids. 

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The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

The mechanism of action of U ions remains to be fully elucidated. Oiemi-cally, lithium is the lightest of the alkaU metals, which include such biologically important elements as sodium and potassium. Apart from interference with transmembrane cation fluxes (via ion channels and pumps), a lithium effect of major significance appears to be membrane depletion of phosphatidylinositol bisphosphates, the principal lipid substrate used by various receptors in transmembrane signalling (p. 66). 

Einspahr KJ, Thompson GA Jr. Transmembrane signalling via phosphatidylinositol 4,5-bisphosphate hydrolysis in plants. Plant Physiol 1990 93 361-366. 

In summary, transmembrane and intracellular signaling with phosphatidylinositol phosphates is a dynamically expanding field. The progress in this area is critical to understanding the intricate spatiotemporal effects of generation of these small molecular mediators in response to extracellular signals on the functional roles of intracellular proteins. 

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