کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
443834 692779 2008 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Functional and structural characterization of PKA-mediated pHi gating of ROMK1 channels
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی تئوریک و عملی
پیش نمایش صفحه اول مقاله
Functional and structural characterization of PKA-mediated pHi gating of ROMK1 channels
چکیده انگلیسی

Hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS) is a severe salt-losing renal tubular disorder and results from the mutation of renal outer medullary K+ (ROMK1) channels. The aberrant ROMK1 function induces alterations in intracellular pH (pHi) gating under physiological conditions. We investigate the role of protein kinase A (PKA) in the pHi gating of ROMK1 channels. Using giant patch clamp with Xenopus oocytes expressing wild-type and mutant ROMK1 channels, PKA-mediated phosphorylation decreased the sensitivity of ROMK1 channels to pHi. A homology model of ROMK1 reveals that a PKA phosphorylation site (S219) is spatially juxtaposed to the phosphatidylinositol 4,5-bisphosphate (PIP2) binding residues (R188, R217, and K218). Molecular dynamics simulations suggest a stable transition state, in which the shortening of distance between S219 and R217 and the movement of K218 towards the membrane after the PKA-phosphorylation can be observed. Such conformational change may bring the PIP2 binding residues (K218) more accessible to the membrane-bound PIP2. In addition, PIP2 dose-dependently reactivates the acidification-induced rundown channels only when ROMK1 channels have been phosphorylated by PKA. This implies a sequence regulatory episode reflecting the role of PIP2 in the pHi gating of ROMK1 channels by PKA-mediated phosphorylation. Our results provide new insights into the molecular mechanisms underlying the ROMK1 channel regulation associated with HPS/aBS.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Graphics and Modelling - Volume 27, Issue 3, October 2008, Pages 332–341
نویسندگان
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