A novel neuroendocrine intracellular signaling pathway.
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Expression of many components of the secretory pathway in peptidergic neuroendocrine cells is precisely controlled in response to secretagogues. Regulated endocrine-specific protein (RESP18) was identified as a dopamine-regulated intermediate pituitary transcript. Although the amino acid sequence of RESP18 initially suggested that it might be a novel preprohormone, its widespread expression in peptide-producing neurons and endocrine cells and its localization to the lumen of the endoplasmic reticulum suggested that it subserves a unique function. Subtractive hybridization of a pituitary corticotrope AtT-20 cell line engineered for inducible RESP18 expression demonstrated a RESP18-dependent induction of several transcripts. Regulation of RESP18 expression in vitro and in vivo was accompanied by changes in the same transcripts. Several cDNAs encoding transcripts up-regulated by RESP18 were analyzed by DNA sequencing, searching the GenBank databases for homologous proteins, and Northern blotting. One novel clone showed a tissue distribution nearly identical to that of RESP18. One clone was identical to rat LIMK2, a protein kinase containing modular protein-protein interaction LIM (lin-11, isl-1, mec-3) domains. Another clone was similar to monomeric bacterial isocitrate dehydrogenases. Like the unfolded protein response, these data demonstrate a novel signaling pathway from the secretory pathway lumen to the nucleus. RESP18 acts as a lumicrine peptide (an intracellular luminal autocrine hormone) inducing this pathway.
Amino acid sequence; Animals; Biosynthesis; Cell lines; Clone cells; Cytology; Dopamine; Dopamine Agents/pharmacology; Genetics; Genetic transcription; Male; Men; Mixed Function Oxygenases/genetics; Molecular Sequence Data; Multienzyme complexes; Nerve tissue proteins; Nerve Tissue Proteins/biosynthesis; Nerve Tissue Proteins/chemistry; Neurosecretory Systems; Nucleic acid hybridization; Oxygenases; Pituitary gland; Pituitary Gland/cytology; Pituitary Gland/drug effects; Proteins—Synthesis; Rats; Rats; Sprague-Dawley; Second Messenger Systems/genetics; Sequence Homology; Amino Acid; Transcription; Genetic/drug effects
Life Sciences | Medicine and Health Sciences | Molecular Biology | Neurosciences
Schiller, M. R.,
Mains, R. E.,
Eipper, B. A.
A novel neuroendocrine intracellular signaling pathway..
Molecular Endocrinology, 11(12),