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The RCK2 domain uses a coordination site present in Kir channels to confer sodium sensitivity to Slo2.2 channels.

ABSTRACT: Slo2 Na(+)-activated potassium channels are widely expressed in neurons and other cells, such as kidney, heart, and skeletal muscle. Although their important physiological roles continue to be appreciated, molecular determinants responsible for sensing intracellular Na(+) remain unknown. Here we report identification of an Na(+) regulatory site, similar to an Na(+) coordination motif described in Kir channels, localized in the RCK2 domain of Slo2.2 channels. Molecular simulations of the homology-modeled Slo2.2 RCK2 domain provided structural insights into the organization of this Na(+) coordination site. Furthermore, free energy calculations reproduced the experimentally derived monovalent cation selectivity. Our results suggest that Slo2.2 and Kir channels share a similar mechanism to coordinate Na(+). The localization of an Na(+) sensor within the RCK2 domain of Slo2.2 further supports the role of RCK (regulators of conductance of K(+)) domains of Slo channels in coupling ion sensing to channel gating.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC3277328 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Natural killer (NK) cells are key participants in the innate immune response. Killer cell immunoglobulin-like receptors (KIRs) are involved in the activation and inhibition of NK cells through the recognition of human leukocyte antigen (HLA) class I molecules. We investigated the impact of KIR/HLA combinations on susceptibility and long-term clinical outcome in Japanese patients with type 1 autoimmune hepatitis (AIH). Methods:A total of 154 cases of AIH were recruited at Shinshu University Hospital between 1974 and 2018. KIR genes and HLA class I and II alleles were genotyped in all patients along with 201 healthy individuals. Associations between KIR/HLA pairs and clinical outcomes (liver decompensation and liver-related death) were evaluated using the Cox proportional hazards model with stepwise method. Results:After a median follow-up period of 11.1 years, 12% of patients experienced liver decompensation and 8% died from liver disease. KIR3DL1/HLA-B Bw4-80Ile (p = 0.0062) and the HLA-DRB1*04:05-DQB1*04:01 haplotype (p ?0.001) were significantly associated with AIH. Conversely, significant protective associations were found for KIR3DL1/HLA-B Bw4-80Thr (p = 0.0092) and KIR2DL1/HLA-C2 (p = 0.0025). The KIR3DL1/HLA-B Bw4-positive phenotype was strongly associated with a favorable clinical outcome (liver decompensation: hazard ratio [HR] 0.37, p = 0.037; liver-related death: HR 0.26, p = 0.038). Cirrhosis was detected in 16 (10%) patients at diagnosis and was significantly related to poor survival (HR 17.87, p ?0.001) and progression to liver decompensation (HR 9.00, p ?0.001). Conclusions:This study revealed the impact of specific KIR/HLA pairs in AIH susceptibility and progression in Japanese patients. KIR3DL1/HLA-B Bw4-negative patients with AIH and cirrhosis at diagnosis are at high risk of adverse outcomes and require careful surveillance. Lay summary:Autoimmune hepatitis (AIH) is a disease of the liver that can present in acute or chronic hepatitis. We examined whether KIR/HLA pairs were associated with AIH susceptibility or disease progression. KIR3DL1/HLA-B Bw4 was a novel KIR/HLA pair related to a favorable clinical outcome, while cirrhosis at the initial diagnosis was a risk factor for poor prognosis. Thus, frequent and careful surveillance is advised for KIR3DL1/HLA-B Bw4-negative patients with AIH and cirrhosis.

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The RCK2 domain uses a coordination site present in Kir channels to confer sodium sensitivity to Slo2.2 channels.

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