ANALYSIS OF THE EXCITATORY ACTION OF ATP

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Cell surface receptors for extracellular adenosine triphosphate (ATP) are found on developing chick skeletal muscle fibers, both in vitro and in vivo. These channels are coupled to two classes of ion channels. The goals of this study are to understand the cellular and molecular basis by which ATP activated channels operate, and to determine the function of these channels in developing skeletal muscle. Since ATP is present in cholinergic vesicles at high concentration, one possibility is that there may be purinergic, as well as cholinergic transmission at developing neuromuscular junctions. A second possibility is that ATP may be released from some myoblasts, and interact with receptors on other myoblasts to promote muscle differentiation. The specific aims for the current grant period are: 1) To identify the second messenger molecule that couples ATP receptors to the activation of a late potassium current. These experiments seem likely to result in the description of a new second messenger, or in the description of novel way that a known second messenger can affect ion channel function. 2) To compare the response of chick skeletal muscle to ATP with the responses of mammalian skeletal muscle and avian smooth muscle. If responses to ATP like those seen in chick skeletal muscle are found to be widespread, it will greatly increase the likelihood that the unusual properties of the ATP-activated channels endows the system with a special function. 3) To test the hypotheses that ATP receptors play an essential role in myoblast fusion or during synaptogenesis. These experiments will test the two most likely roles that ATP receptors might play in developing muscle. 4) To determine how cell-cell interactions regulate the expression of the ATP receptors. These experiments will allow us to determine whether two receptors that are expressed in the same tissue, ATP receptors and acetylcholine receptors, are regulated independently, or in a coordinated manner. The problem of the regulation of multiple receptors is faced by virtually all cells of the central nervous system. The issue can now be studied in an accessible system. 5) To initiate studies that will ultimately lead to the biochemical and molecular characterization of the ATP receptor. Knowledge of the cellular interactions that control normal muscle development will provide a basis for understanding, and perhaps ameliorating, medically relevant deficits in nerve and muscle function.