Proteolysis in Neuropeptide Processing and Other Neural Functions

Loh, Y. Peng; Brownstein, Michael J.; Gainer, Harold

doi:10.1146/annurev.ne.07.030184.001201

Cited by 265 publications

(47 citation statements)

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“…In neuronal and endocrine cells, many peptide hormones are synthesized from larger precursors, prohormones, through endoproteolytic cleavage at paired basic amino acids during intracellular transport [ 1,2]. These cells have two secretory pathways: a regulated pathway by which peptide hormones are selectively segregated into secretory granules and stored until their release is stimulated by secretagogues, and a constitutive pathway by which other proteins are secreted continuously without storage U-51.…”

Section: Introductionmentioning

confidence: 99%

Prorenin is sorted into the regulated secretory pathway independent of its processing to renin in mouse pituitary AtT‐20 cells

et al. 1989

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A native human prorenin and a mutant of its processing site (Arg-43 to Gln) were expressed in mouse pituitary AtT-20 celh which process prorenin to renin and have both regulated and constitutive secretory pathways. The native prorenin was processed to renin and secreted in a regulated manner. Although the mutant precursor was not processed, it was also secreted in a regulated manner. These results suggest that prorenin is sorted into the regulated pathway, stored in secretory granules and released by stimulus whether it is processed to renin or not.

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Section: Introductionmentioning

confidence: 99%

Prorenin is sorted into the regulated secretory pathway independent of its processing to renin in mouse pituitary AtT‐20 cells

et al. 1989

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“…Peptide hormones and neuropeptides are synthesized as larger percursors (1). These precursors (prohormones) are transported from the rough ER, the site of synthesis, to the cis and then the trans-Golgi network, where they are sorted and packaged into the granules of the regulated secretory pathway.…”

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confidence: 99%

Intracellular misrouting and abnormal secretion of adrenocorticotropin and growth hormone in Cpe ^fat mice associated with a carboxypeptidase E mutation

Shen

Loh

1997

Proc. Natl. Acad. Sci. U.S.A.

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Cpe fat mice carry a mutation in the carboxypeptidase E͞H gene which encodes an exopeptidase that removes C-terminal basic residues from endoproteolytically cleaved hormone intermediates. These mice have endocrine disorders including obesity, infertility, and hyperproinsulinemia-diabetes syndrome, but the etiology remains an enigma. Because studies have identified membrane carboxypeptidase E as a sorting receptor for targeting prohormones to the regulated secretory pathway for processing and secretion, the intracellular routing and secretion of pro-opiomelanocortin͞ adrenocorticotropin and growth hormone from anterior pituitary cells were investigated in Cpe fat mice. In Cpe fat mice, pro-opiomelanocortin was accumulated 24-fold above normal animals in the pituitary and it was poorly processed to adrenocorticotropin. Furthermore, pro-opiomelanocortin was secreted constitutively at high levels, showing no response to stimulation by corticotropin-releasing hormone. Similarly, growth hormone release was constitutive and did not respond to high K ؉ stimulation. Both pro-opiomelanocortin and growth hormone levels were elevated in the circulation of Cpe fat mice versus normal mice. These data provide evidence that the lack of carboxypeptidase E, the sorting receptor, results in the intracellular misrouting and secretion of proopiomelanocortin and growth hormone via the constitutive pathway in the pituitary of Cpe fat mice.

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“…Lines of genetic evidence [8 -121 and studies using synthetic analogs [13 -151 and site-directed mutants [16 -201 of prohormones have suggested that paired basic amino acids are essential for prohormone processing. However, little is known about the specificity of endoprotease responsible for the precursor cleavage; precursor proteins often contain basic pairs which are never cleaved and tissue-specific use of certain pairs is often observed [2,4]. It has been recently reported by surveying various prohormone sequences that there is a hierarchy for the use of certain pairs of basic amino acids at the cleavage sites [17,21] : Lys-Arg (70%); Arg-Arg (1 5 % ) ; Lys-Lys (10%); Arg-Lys (5%).…”

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Sequence requirements for prohormone processing in mouse pituitary AtT‐20 cells

Nagahama

Nakayama

Murakami

1991

European Journal of Biochemistry

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Although cleavage of peptides at sites marked by paired basic amino acids is a common feature of prohormone processing, little is known about the properties of endoprotease(s) responsible for cleavage of the precursor. To examine the cleavage specificity of a processing endoprotease, we have altered the Lys-Arg cleavage site of human prorenin to Arg-Arg, Lys-Lys and Arg-Lys by site-directed mutagenesis, and expressed the native and mutated precursors in mouse pituitary AtT-20 cells which are known to process foreign prohormones, including prorenin, at paired basic sites during the regulated secretory process. All native and mutated human prorenins were sorted into the regulated secretory pathway. The mutated precursor with Arg-Arg instead of the Lys-Arg native pair was processed at about half the efficiency of the native one, while the Lys-Lys and Arg-Lys mutants were not processed. Rat prorenin, which naturally has a Lys-Lys pair, was not processed in the cells. In addition, mouse Ren2 prorenin, which has a Ser residue next to the Lys-Arg pair, but not mouse Renl prorenin, which has a Pro residue next to the pair, was processed. These results suggest that the Arg residue at the COOH side of the basic pair is essential for cleavage of prorenins by a processing enzyme during the regulated secretory process in AtT-20 cells, although the NH,-side Lys residue also plays a role. The results also demonstrate that the processing enzyme cannot cleave the Arg-Pro peptide bond.In endocrine and neuronal cells, many peptide hormones and neuropeptides are produced from larger, biologically inactive precursors through endoproteolytic cleavage, usually, at paired basic amino acids during intracellular transport [l -41. These cells have two secretory pathways. One is the regulated pathway by which mature hormones are produced by prohormone processing and are selectively targeted to secretory granules where they are stored until release is stimulated. The other is the constitutive pathway by which other proteins are secreted continuously without storage [5 -71. Lines of genetic evidence [8 -121 and studies using synthetic analogs [13 -151 and site-directed mutants [16 -201 of prohormones have suggested that paired basic amino acids are essential for prohormone processing. However, little is known about the specificity of endoprotease responsible for the precursor cleavage; precursor proteins often contain basic pairs which are never cleaved and tissue-specific use of certain pairs is often observed [2,4]. It has been recently reported by surveying various prohormone sequences that there is a hierarchy for the use of certain pairs of basic amino acids at the cleavage sites [17,21] : Lys-Arg (70%); Arg-Arg (1 5 % ) ; Lys-Lys (10%); Arg-Lys (5%). The data suggest that processing enzymes may have a preference for cleavage on the COOH side of Arg residues.Mouse pituitary AtT-20 cells, which endogenously produce adrenocorticotropin, P-endorphin, etc., through cleavage of a precursor, pro-opiomelanocortin, during the regulated secretor...

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Proteolysis in Neuropeptide Processing and Other Neural Functions

Cited by 265 publications

References 68 publications

Prorenin is sorted into the regulated secretory pathway independent of its processing to renin in mouse pituitary AtT‐20 cells

Prorenin is sorted into the regulated secretory pathway independent of its processing to renin in mouse pituitary AtT‐20 cells

Intracellular misrouting and abnormal secretion of adrenocorticotropin and growth hormone in Cpe ^fat mice associated with a carboxypeptidase E mutation

Sequence requirements for prohormone processing in mouse pituitary AtT‐20 cells

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Proteolysis in Neuropeptide Processing and Other Neural Functions

Cited by 265 publications

References 68 publications

Prorenin is sorted into the regulated secretory pathway independent of its processing to renin in mouse pituitary AtT‐20 cells

Prorenin is sorted into the regulated secretory pathway independent of its processing to renin in mouse pituitary AtT‐20 cells

Intracellular misrouting and abnormal secretion of adrenocorticotropin and growth hormone in Cpe fat mice associated with a carboxypeptidase E mutation

Sequence requirements for prohormone processing in mouse pituitary AtT‐20 cells

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Intracellular misrouting and abnormal secretion of adrenocorticotropin and growth hormone in Cpe ^fat mice associated with a carboxypeptidase E mutation