Channelopathy of small-and intermediate-conductance Ca^(2+)-activated K^(+)channels  

作　　者：Young-Woo Nam Myles Downey Mohammad Asikur Rahman Meng Cui Miao Zhang 

机构地区：[1]Department of Biomedical and Pharmaceutical Sciences,Chapman University School of Pharmacy,Irvine,CA 92618,USA [2]Department of Pharmaceutical Sciences,Northeastern University School of Pharmacy,Boston,MA 02115,USA

出　　处：《Acta Pharmacologica Sinica》2023年第2期259-267,共9页中国药理学报（英文版）

基　　金：supported by a Scientist Development Grant 13SDG16150007 from American Heart Association,a YI-SCA grant from National Ataxia Foundation,and a grant 4R33NS101182-03 from NIH.

摘　　要：Small-and intermediate-conductance Ca^(2+)-activated K^(+)(K_(Ca)2.x/K_(Ca)3.1 also called SK/IK)channels are gated exclusively by intracellular Ca^(2+).The Ca^(2+)binding protein calmodulin confers sub-micromolar Ca^(2+)sensitivity to the channel-calmodulin complex.The calmodulin C-lobe is constitutively associated with the proximal C-terminus of the channel.Interactions between calmodulin N-lobe and the channel S4-S5 linker are Ca^(2+)-dependent,which subsequently trigger conformational changes in the channel pore and open the gate.KCNN genes encode four subtypes,including KCNN1 for K_(Ca)2.1(SK1),KCNN2 for K_(Ca)2.2(SK2),KCNN3 for K_(Ca)2.3(SK3),and KCNN4 for K_(Ca)3.1(IK).The three K_(Ca)2.x channel subtypes are expressed in the central nervous system and the heart.The K_(Ca)3.1 subtype is expressed in the erythrocytes and the lymphocytes,among other peripheral tissues.The impact of dysfunctional K_(Ca)2.x/K_(Ca)3.1 channels on human health has not been well documented.Human loss-of-function K_(Ca)2.2 mutations have been linked with neurodevelopmental disorders.Human gain-of-function mutations that increase the apparent Ca^(2+)sensitivity of K_(Ca)2.3 and K_(Ca)3.1 channels have been associated with Zimmermann-Laband syndrome and hereditary xerocytosis,respectively.This review article discusses the physiological significance of K_(Ca)2.x/K_(Ca)3.1 channels,the pathophysiology of the diseases linked with K_(Ca)2.x/K_(Ca)3.1 mutations,the structure–function relationship of the mutant K_(Ca)2.x/K_(Ca)3.1 channels,and potential pharmacological therapeutics for the K_(Ca)2.x/K_(Ca)3.1 channelopathy.

关 键 词：CHANNELOPATHY K_(Ca)2.2 channels K_(Ca)2.3 channels K_(Ca)3.1 channels Zimmermann-Laband syndrome hereditary xerocytosis 

分 类 号：R73[医药卫生—肿瘤]