Membrane trafficking and the regulation of NKCC2.
Membrane trafficking and the regulation of NKCC2.
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NKCC2 的膜运输和调控。
DOI：
10.1152/ajprenal.00410.2005
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Mount,DavidB
中科院分区：
文献类型：
--
作者：
Mount,DavidB
+-K+-2CL J COTRANSPORTER of the thick ascending limb (TAL; NKCC2) plays a critical role in the countercurrent multiplication mechanism that drives urinary concentration in response to vasopressin (16). The paper by Ortiz (20) in this issue of AJP-Renal Physiology nicely complements prior work on the regulation of NKCC2 by vasopressin and cAMP, highlighting the role of transporter trafficking in the acute response to this hormone. The NKCC2 protein, also known as BSC-1, is encoded by the SLC12A1 gene, a member of the cation-chloride cotransporter gene family (12). Heterologous expression of NKCC2 in Xenopus laevis oocytes reveals the expected functional characteristics, ie, diuretic-sensitive cotransport of Na+(26) and K+(86Rb+)(7) that is Cl J dependent. Notably, alternative splicing of three cassette exons in SLC12A1 generates isoforms that differ in both distribution along the TAL (13) and in the sequence of transmembrane domain 2 and a flanking intracellular loop (22). These three isoforms differ dramatically in their affinity for the three transported ions (10, 25), leading to novel insights into the mechanism of ion transport by this important transporter (6). NKCC2 is activated about twofold by cell shrinkage, due, at least in part, to phosphorylation of a cluster of NH2-terminal threonines (8) that were initially identified in NKCC1 (SLC12A2)(2), the widely expressed “secretory” Na+-K+-2Cl J cotransporter. Unfortunately, regulatory characterization of NKCC2 is of necessity limited to X. laevis oocytes; attempts by at least two groups have failed repeatedly to express this transporter in mammalian cells, in contrast to the success in expressing other cation-chloride cotransporters in HEK293 cells (21, 23) and Madin-Darby canine kidney cells (29). As a consequence, considerably less is known about the cell biology and posttranscriptional regulation of NKCC2 than that of aquaporin-2 (1) and other key renal transport proteins. Luminal absorption of Na+-Cl J via NKCC2 conspires with the low water permeability of the TAL and the countercurrent mechanism to increase medullary tonicity, thus facilitating water absorption by the collecting duct. Vasopressin has both long-term and short-term effects on NKCC2 expression and function, resulting in an enhancement of countercurrent multiplication (16). Subjecting rats to moderate water restriction or DDAVP treatment for 7 days thus results in an increase in the expression of NKCC2 (15). Long-term increases in cAMP presumably stimulate NKCC2 expression via a cAMP response element in the SLC12A1 promoter (4, 14). Several hormones other than vasopressin serve to increase cAMP in the TAL; these include parathyroid hormone, glucagon, and calcitonin (3). In contrast, coupling of the calcium-sensing receptor and the EP3 prostaglandin receptor to inhibitory G proteins is thought to reduce cAMP generation in the TAL (27), leading to a reduction in NKCC2 expression (5, 28). Vasopressin has well-documented acute effects on NKCC2, activating apical Na+-K+-2Cl J cotransport (18) within minutes in perfused TAL (11). Immunoelectron microscopy by Nielsen et al.(19) indicated the expression of NKCC2 protein at the plasma membrane of TAL cells and in abundant subapical vesicles, suggesting a potential role for membrane translocation of the transporter in the acute response to vasopressin/cAMP. More recently, Gimenez and Forbush (9) demonstrated acute phosphorylation of NKCC2 in vivo in response to vasopressin, using a phosphospecific antibody that recognizes the phosphorylated threonines mentioned above (8). This was accompanied by a 55% increase in immunoreactive NKCC2 protein …
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DOI：
10.1016/0002-9149(81)90222-8
发表时间：
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期刊：
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