[Frontiers in Bioscience 2, d88-125, March 1, 1997]

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Bianca Marchetti

Department of Pharmacology, Medical School, University of Catania, 95125 Catania, Laboratory of Biotech. Neuropharmacology, OASI Institute for Research and Care (IRCCS) on Mental Retardation and Brain Aging (IRCCS) Troina, (EN), Italy.

Received 8/2/96; Accepted 2/20/97; On-line 3/1/97

5. The Second Messenger System and Transcription Factor Network

The vast majority of the signaling molecules coupled to astrocyte receptors are linked to the stimulation of the protein kinase A (PKA) pathway through activation of adenylyl cyclase and elevation of cAMP levels. A second pathway is represented by the hydrolysis of inositol-containing phospholipids, generating diacylglycerol (DAG).

DAG, can be further metabolized to arachidonic acid (AA), and thus form a substrate for eicoisanoid production (Fig. 6). Indeed, agonist evoked release of unmetabolized AA could be significant not only for substrate supply for further metabolism, but also for "inter-cellular" signaling and cross-talk (see 116-119, for reviews).

Figure 6. Dynamic interaction between the astroglial cell compartment, the endothelial and the neuronal cell. Upon selective stimulation astrocytes may release products able to alter the vascular endothelium. The expression of receptors on astrocytes, their ability to synthesize vasoactive products, and the close spatial relationships of these cells both with neurons and cell of the vasculature implicate astroglial cells in bi-directional signaling processes in the CNS (see 116, 117). PG: prostaglandin, PAF: platelet activating factor, TXA2: tromboxane , NO: nitric oxide, ATP: adenosine triphosphate, ADRF (NO): astrocyte-derived (vaso)-relaxing factor (nitric oxide). The potential interaction between the growths factors released by the astroglial compartment and LHRH released by neuron terminals is also illustrated.

Insulin-like growth factor and other members of the GF family, belong to the family of transmembrane signal-transduction tyrosine kinases. Evidence has accumulated suggesting that the effect of these GFs on a number of cell types is mediated by tyrosine phosphorylation of a variety of cellular proteins including phospholipase C, which leads to the formation of inositol 1, 4, 5-triphosphate (120, 121). In addition to membrane receptors that transduce their biological effects, IGF and other GFs associate with multiple high affinity binding proteins that can modify peptide receptor interactions (89, 90, 122). Moreover, specific cytoskeletal proteins such as actin, vinculin, alpha-actin, and myosin could also serve as substrate for tyrosine phosphorylation (123). Supporting evidence for astroglial cell production of a nitrosyl factor, endothelium-derived relaxing factor (EDRFs), and for its autocrine effect has come from a number of recent reports (see 118, 119). Using an antiserum against arginine, it has been demonstrated that astrocytes are the main store of nitrosyl factor, i.e. NO, in the brain (see 119). Moreover, it was found that norepinephrine (NE) increases astrocyte cGMP by a mechanism dependent upon synthesis of NO (see 116, 117), and that astrocytes contain inducible NO synthase activity (see Murphy et al. 1992). Indeed, endothelial cells, macrophages and astrocytes have been reported to express both constitutive and inducible NOS activity. Since a number of studies support the notion that glial cells can respond to NO via soluble guanylyl cyclase present in astrocytes and also contribute to the production of NO in the brain and in view of the fact that the conditioned medium of astrocytes stimulated by a number substances (calcium ionophores, noradrenaline, and glutamate) may contain NO (see 116), then the intermediacy of astrocyte-derived NO may be claimed in a number of neurotransmitter-induced CNS functions.