The overall goal of this research program is to investigate the pharmacological and biochemical properties of neurotransmitter receptors. Studies are proposed to investigate the regulation of receptors for dopamine, excitatory amino acids, opiate peptides, and somatostatin, and of mechanisms through which signal transduction occurs. A multidisciplinary approach is proposed. Thus, morphological techniques, including quantitative autoradiography, in situ hybridization, in situ transcription, and immunocytochemistry, will be used to assess the cellular and anatomical distribution of receptors and GTP-binding regulatory proteins (G proteins). The ultimate consequence of receptor-mediated activation or inhibition in the central nervous system is a change in behavior. A variety of behavioral paradigms will be explored to investigate the role of specific classes of dopamine receptors in regulating behavioral responses. In other experiments, the molecular consequences of the chronic administration of opiates will be explored. The results of these studies may contribute to our understanding of the development of cellular tolerance. A variety of biochemical and molecular biological approaches will be used to investigate the properties of receptors and G proteins. Studies involving the binding of radioligands will emphasize the use of subtype-selective ligands to investigate the effects of pharmacological manipulations and endogenous modulators on the densities and properties of receptors. Studies of the purification of receptors using conventional and affinity chromatographic techniques are proposed as are experiments designed to clone receptors by low-stringency hybridization screening of libraries, through the use of the polymerase chain reaction, by expression of size-selected mRNA in Xenopus oocytes, or by using a recently developed subtraction hybridization scheme called differential amplification. Experiments are described to investigate the mechanisms involved in the coupling of receptors for the biogenic amine dopamine, for somatostatin, for opiate peptides, and for excitatory amino acids with different cellular effector systems. In particular, attempts will be made to identify the G proteins coupling these different receptors to their cellular effector systems. Studies of receptor-linked effector mechanisms will include investigations of receptors that induce changes in adenylyl cyclase activity, in phosphatidylinositol metabolism, and in membrane conductance and ion permeability. The distribution of G proteins within the plasma membrane and other subcellular structures will be examined, and structure-activity relationships will be defined. Among the electrophysiological approaches to be used are the whole-cell patch-clamp techniques. Studies to investigate the role of G proteins in signal transduction will be carried out. These will involve the use of antibodies directed against subtypes of G proteins and studies involving reconstitution of functional responses with purified G proteins. Examination of different receptor systems and the mechanisms through which their properties are regulated may help to elucidate common mechanisms that permit different receptors to interact in a coordinated manner to elicit specific physiological and behavioral responses.

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National Institute of General Medical Sciences (NIGMS)
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University of Pennsylvania
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