מתוך medicontext.co.il
By Will Boggs, MD
NEW YORK (Reuters Health) – Polycystin-2, the product of the gene that is mutated in type 2 autosomal dominant polycystic kidney disease (ADPKD), functions as a calcium-activated intracellular calcium release channel, according to a report in the February 18th advance online issue of Nature Cell Biology.
Previous research linked mutations in either of two genes, PKD1 or PKD2, to ADPKD, the authors explain, but the mechanisms and sites of action of polycystin-1 and -2 (the respective gene products) have yet to be elucidated.
Dr. Stefan Somlo, from Yale University School of Medicine in New Haven, Connecticut, and colleagues examined both the mechanism and site of action of polycystin-2 in porcine kidney cell lines and in mouse kidneys.
Cells expressing a truncated mutant polycystin-2 were less sensitive to channel activation than were cells expressing wild-type polycystin-2, the authors report, and endoplasmic reticulum vesicles from cells expressing a pathogenic missense mutant showed no currents.
"These data," the investigators say, "suggest that polycystin-2 functions as a calcium-activated intracellular calcium release channel in vivo and that polycystic kidney disease results from the loss of a regulated intracellular calcium release signalling mechanism."
"At the level of individual cells, we believe that calcium is acting as the second messenger in PKD protein pathways," Dr. Somlo told Reuters Health. "This signaling is central in the normal functions of the PKD proteins in cells; however, we do not know what the pathways downstream of this calcium signal are."
"I do not think the current study directly suggests treatment," cautioned Dr. Somlo. "However, from a strategic standpoint, it does suggest that if one begins to better understand the calcium channel-mediated signal in PKD, one could think about developing (partial) agonists for this signal that may slow, if not prevent, the growth of cysts. Presumably, slowing the process will help slow progression to renal failure."
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