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Amine uptake and peptide hormone secretion: APUD cells in a new landscape

C. A. R. Boyd

APUD cells were so named by Pearse (1969) as a result of his attempt to produce a synthesis relating a number of observations concerning the histochemistry and function of peptide-secreting endocrine cells, particularly those of the gastrointestinal tract. One of these properties was that peptide-secreting endocrine cells appeared to share an ability to take up precursors of biologically active amines, to produce active amine through subsequent intracellular decarboxylation and then store the amine product in secretory vesicles, hence APUD (amine precursor uptake and decarboxylation). This widespread phenomenon was initially described by Pearse himself (1966) for the calcitonin-secreting parafollicular C cells of dog thyroid using 5-hydroxytryptophan as the amine precursor. In that paper the author noted that such an uptake was also found in other peptide hormone-secreting cells, for example in the corticotrophs of the anterior pituitary gland and in the -cells of the endocrine pancreas. However, these clear-cut observations became hidden beneath the much larger edifice that the APUD concept became, with APUD cells (eventually including more than 40 cell types) defined as a 'diffuse neuroendocrine system ... the third branch of the nervous system acting within the second, the autonomic nervous system in the control of all the intestinal organs' and with a developmental lineage that was defined as necessarily being from neuroectoderm. This monumental hypothesis has not stood the rigour of experimental test using modern methods of cell and developmental biology. However, if the grand theory itself has been found wanting (see for example Andrew et al. 1998), the original observations that led to the idea of the APUD cell have certainly been confirmed and yet have remained neglected for much of the last decade. Why should cells that are undoubtedly peptide-secreting endocrine cells have the general property of handling amines in a way characteristic of neurones?

In this issue of The Journal of Physiology, Blackmore et al. shed a fascinating new perspective on these early findings by showing that functionally the observed pattern of secreted peptide hormones (which emerge as processed fragments from larger polypeptide precursors) results from the ability of these cells to take up amines. The connection arises because of two phenomena which share a common molecular event - in one case the result of, in the other the cause of the link. Because peptide hormone processing is carried out by intracellular endopeptidases within secretory vesicles and because the enzymes responsible for site-specific activity (the pro-hormone convertases) are themselves highly pH sensitive, the pattern of peptide release will necessarily depend upon secretory vesicular pH. Blackmore et al. (2001) have now shown that the pH within this organelle is itself regulated by monoamines through a simple link. Amine transport across the vesicular membrane occurs through transporters that are proton-coupled antiporters. Hence addition of amine to the cell, by activating amine transport and accumulation within the vesicles reduces intravesicular acidification; this alters the processing of secreted peptide, thus establishing the link between amine uptake and peptide hormone secretion.

The conclusion from this study is so unambiguous because of the imaginative combination of modern experimental strategies adopted by the authors. Using confocal microscopy to measure intravesicular pH (with a pH-sensitive green fluorescent protein targeted to secretory vesicles) in cells in situ and pharmacological tools to isolate the contribution of specific vesicular monoamine transporters, the authors make a combined attack using a genetically engineered cell line. A pancreatic -cell line (a nice touch here is that the authors manage to acknowledge materials received from both Drs Banting and Best!) was stably transfected with cDNA constructs expressing both the vesicular monoamine transporter VMAT2 and the peptide hormone precursor progastrin, a peptide that is well known to be cleaved into a number of specific smaller fragments (e.g. G34 and G17) with differing biological effects and properties depending on the specific product released. Moreover gastrin is a peptide for which cleavage-product-specific antibodies have been developed, allowing peptide processing as a function of amine transport-dependent intravesicular pH to be monitored. The results are clear-cut: expression of the vesicular monoamine transporter alters peptide processing in these cells and the mechanism for this coupling does indeed appear to be altered intravesicular pH.

Wilmer (1960) observed in his classic monograph Cytology and Evolution that '... in its evolutionary processes Nature tends to build on what is already present and does so by a continual process of modification. A plurality of purpose may arise as a consequence of some basic embryological processes which probably have an earlier and originally a functional origin'; or as Jacob (see Crick, 1988) put it more succinctly, 'evolution is a tinkerer'. The paper by Blackmore et al. (2001) exemplifies this particularly clearly by showing how a novel process linking neuronal and endocrine cell function emerges from such evolutionary tinkering with the cellular expression and properties of an intracellular vesicular monoamine transporter.

	REFERENCES

ANDREW A., KRAMER, B. & RAWDON, B. B. (1998). Journal of Pathology 186, 117-118.	[Medline]
BLACKMORE C. G., VARRO, A., DIMALINE, R., BISHOP, L., GALLACHER, D. V. & DOCKRAY, G. J. (2001). Journal of Physiology 531, 605-617.	[Abstract/Full Text]
CRICK F. H. C. (1988). What Mad Pursuit, pp. 5-6. Basic Books, New York
PEARSE A. G. E. (1966). Nature 211, 598-600.	[Medline]
PEARSE A. G. E. (1969). Journal of Histochemistry and Cytochemistry 17, 303-313.	[Medline]
WILMER E. N. (1960). Cytology and Evolution. Academic Press, London

This Article Abstract Full Text (PDF) Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Boyd, C. A. R. Search for Related Content PubMed PubMed Citation Articles by Boyd, C. A. R. Related Collections Perspectives