We are continuing to study the structural and genetic basis for generating the diversity of neuropeptide/neurotransmitter phenotypes found in the nervous and endocrine systems. This work involves I) analysis of cis- acting elements determining cell-specific expression and regulation of neuropeptide genes and II) characterization of components of neuropeptide/neurotransmitter vesicles responsible for packaging of neurotransmitters and neuropeptides in neuroendocrine cells. 1) Enkephalin gene regulation in chromaffin cells by protein kinases C and A, and by calcium, and galanin gene regulation in chromaffin cells appear to be mediated by proteins that bind specific sequences within the enkephalin and galanin gene promoters, and that can also be bound by AP-1 consensus motifs, but behave differently from the proteins fos and jun which commonly bind these DNA regulatory motifs in other endocrine and non- endocrine cells. 2) Second messenger signalling pathways appear to act combinatorially to allow difference ratios of neuropeptides to be expressed in chromaffin cells, and this type of regulation may provide an explanation for the many combinations of neuropeptide co-expression seen throughout the neuroendocrine system. 3) Mutational analysis of the vesicular catecholamine transporter has been initiated to determine the structural basis for biogenic amine uptake, and the subsequent biogenic amine transmitter phenotype of cells expressing various members of the biogenic amine vesicular transporter protein family. 4 Chromogranin A, a component of neuropeptide-containing secretory vesicles has been found to be expressed in virtually all neuronal cells of the central and peripheral nervous systems, implying a generalized role for this protein in neuropeptide-containing neuroendocrine cells. The discovery of chromogranin in non-endocrine secretory cells, such as keratinocytes of the skin, suggest that the role of chromogranin A in peptide/protein secretion may be even more general that previously envisioned.
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