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A Mysterious Mechanism for Promoting Anion Conductance

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Science's STKE  10 Oct 2006:
Vol. 2006, Issue 356, pp. tw347
DOI: 10.1126/stke.3562006tw347

Proteins in the chloride channel, calcium-activated (CLCA) family have been implicated as playing a role in diseases that involve dysfunction of epithelial secretion, such as asthma and cystic fibrosis, and have been shown to mediate a calcium-activated chloride conductance. Mundhenk et al. used immunoprecipitation with antibodies directed against either the N or tagged C terminus at different times after [35S]methionine labeling, as well as Western analysis, to investigate the processing and secretion of murine ClCA3 (mCLCA3) transiently transfected into COS-1 or human embryonic kidney (HEK) 293 cells. mCLCA3 is cleaved into N-terminal and C-terminal products, and the authors found that both cleavage products were secreted and that they coprecipitated from both cell lysates and cell culture medium. Both products were glycosylated. Confocal immunofluorescence analysis indicated that the N-terminal and C-terminal products colocalized in intracellular vesicles and that mCLCA3 fluorescently tagged at the C terminus colocalized with markers for the Golgi and the endoplasmic reticulum. Neither the N-terminal nor the C-terminal product was observed in association with the plasma membrane. Thus, the authors conclude that mCLCA3, which elicits a calcium-activated chloride conductance when expressed in HEK293 cells, does not itself encode a transmembrane anion channel but rather encodes secreted products that may act as signaling molecules to regulate anion channel function.

A second study indicated that another member of the same protein family, human CLCA2, probably does not itself form a channel either.

L. Mundhenk, M. Alfalah, R. C. Elble, B. U. Pauli, H. Y. Naim, A. D. Gruber, Both cleavage products of the mCLCA3 protein are secreted soluble proteins. J. Biol. Chem. 281, 30072-30080 (2006). [Abstract] [Full Text]

R. C. Elble, V. Walia, H.-C. Cheng, C. J. Connon, L. Mundhenk, A. D. Gruber, B. U. Pauli, The putative chloride channel hCLCA2 has a single C-terminal transmembrane segment. J. Biol. Chem. 281, 29448-29454 (2006). [Abstract] [Full Text]

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