While glial cells outnumber neurons in the central nervous system (CNS) by as much as ten to one, relatively little is known about their function. Because it has not been possible to monitor astroglial cell responses to stimuli in vivo, it has been assumed that they function as passive partners in the CNS by providing nutrients and growth factors and maintaining homeostatic conditions in the extracellular spaces. Experiments with astrocytes in primary culture have made it clear that these cells have receptors for neurotransmitters that regulate intracellular second messengers. We have demonstrated that astroglial cells can respond to neurotransmitters by releasing the amino acid taurine -- a putative inhibitory transmitter in the brain. Activation of multiple receptors results in integrated responses. These results have lead us to hypothesize that astroglial cells may participate as active partners in the CNS controlling neuronal activity as integral members of local inhibitory feedback loops. The experiments described in this proposal are designed to extend our knowledge of receptor-mediated release in three ways. First we will describe in detail the receptor- mediated release of a second class of putative transmitters-adenosine and related compounds. Adenosine is also an inhibitory transmitter in the CNS. We have recently observed the release of these compounds from astroglial cells in culture. Second, we will describe the ion dependency and substrate selectivity of release for taurine and adenosine and related compounds and compare these results with similar observation on uptake to indicate if the same mechanisms may be responsible for both uptake and release. Third, we will describe cAMP-dependent protein phosphorylation and determine which phophorproteins are involved in release. Finally, we will isolate and characterize these phosphoproteins in order to better understand how release is regulated. These studies will describe the basic cellular mechanisms regulating release and should lead us to the development of strategies to discern glial from neuronal release of taurine and adenosine and related compounds in the brain.
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