鉀氯離子共同傳輸蛋白是一個藉由同時向胞外運送鉀離子、氯離子及水分子，來調節細胞體積，維持細胞滲透壓恆定的重要膜蛋白，並且與一些人類疾病有關。例如第三型鉀氯離子會在基因缺損的狀態下，表現許多神經症狀。然而，第三型鉀氯離子共同傳輸蛋白在神經的角色仍不明。本研究著重於第三型鉀氯離子共同傳輸蛋白於週邊神經的功能，尤其是神經衝動在運動神經上的傳導。
為探討第三型鉀氯離子共同傳輸蛋白在週邊神經的功能，我們首先了解其在週邊神經上的表現。第三型鉀氯離子共同傳輸蛋白主要位在軸突的蘭式結、許旺細胞的microvilli和paranodal loops。這些位置正是神經衝動傳導發生的位置。使用鉀氯離子共同傳輸蛋白抑制劑，可以抑制compound motor action potential的振幅大小，這個抑制效果與劑量相關且是可逆的，而抑制而鈉鉀氯離子共同傳輸蛋白抑制劑則無法有此作用。這個結果暗示，鉀氯離子共同傳輸蛋白的活性與神經衝動的傳遞有關。我們在
第三型鉀氯離子共同傳輸蛋白的基因剔除小鼠身上，也利用神經傳導檢查，發現了相同的現象。然而，一般的神經傳導檢查並沒有辦法提供足夠的資訊以解釋其機轉。因此，我們利用閾值追蹤的方法，進一步探討缺乏第三型鉀氯離子共同傳輸蛋白造成神經傳導障礙的原因。結果顯示，缺乏第三型鉀氯離子共同傳輸蛋白造成神經興奮性下降和閾值上升。而在超微結構的分析則發現，缺乏第三型鉀氯離子共同傳輸蛋白的神經其paranode的結構異常，這足以造成paranode阻抗下降，而導致蘭氏結的膜閾值上升。這個部分的結果指出了第三型鉀氯離子共同傳輸蛋白對於維持蘭氏結的完整性相當重要。
本研究並且證明了鉀氯離子共同傳輸蛋白相關之嗜中性球吞噬作用對自然免疫的重要性。研究結果顯示，鉀氯離子共同傳輸蛋白，尤其是第三型鉀氯離子共同傳輸蛋白，一方面提供一個氯離子通道，使得氯離子可以流入吞入細菌endosome內，合成具有細胞毒殺作用的HClO，同時並藉由調控phox的膜表現與磷酸化來調節NADPH氧化酶的活性，藉此影響嗜中性白血球的細菌毒殺能力。使用鉀氯離子共同傳輸蛋白抑制劑或用shRNA 抑制其表現，均會使NADPH氧化酶的活性下降。第三型鉀氯離子共同傳輸蛋白基因剔除小鼠之嗜中性球的NADPH氧化酶的活性也是正常小鼠的50%，且其細菌廓清率也比正常小鼠差。由此可知，在活化的嗜中性球，NADPH氧化酶的phox組成，在細胞膜上與鉀氯離子共同傳輸蛋白位在一起，然後一起被胞吞為endosome，在此與活化的NADPH氧化酶共同執行殺菌作用。

K+-Cl- cotransporter (KCC) is a membrane protein which plays an important role in the maintenance of cellular osmotic homeostasis. The dysfunction of KCC has been identified to be associated with several diseases. For example, KCC3-deficient patients and animals show various neurological phenotypes. The mechanisms of KCC3 dysfunction leading to neulogical disorders remain unclear. My PhD research was aimed to study how KCC3 optimizes peripheral nerve function, especially focusing on impulse conduction along motor axons. To study the function of KCC in peripheral nerves, the spatiotemporal expression of KCC was determined. KCCs were mainly expressed on the microvilli of Schwann cells and the axonal node, at which the propagation of action potential occurs. KCC inhibitor, but not NKCC inhibitor, reversibly and dose-dependently diminished the amplitude of compound motor action potentials, suggesting the involvement of KCC activity in the impulse conduction. The KCC3 knockouts showed motor deficits as well as conduction defects in nerve conduction studies (NCS). However, the conventional NCS offered limited information about the mechanisms underlying the impaired conduction. Thus I conducted the axonal excitability study to dissect the mechanisms by which lack of KCC3 compromised nerve conduction. The results demonstrated that KCC3-/- nerves displayed an elevated membrane threshold and a total reduction of excitability. The nodal ultrastructure showed the pathological swollen microvilli and disorganized paranodal loops, which might increase paranodal conductance, alter nodal capacitance and finally diminish axonal excitability. These results highlight the importance of KCC3 in the maintenance of paranodal integrity and optimization of impulse conduction.
In my thesis, I also demonstrated that KCC-dependent neutrophilic phagocytosis is an essential component of innate immunity. Study results showed that KCC constitutes a Cl− permeation pathway and mediates the bactericidal activity by regulating NADPH oxidase activation. Inhibition of KCC activity or knockdown of KCC expression, in particular KCC3, reduced the phosphorylation as well as the membrane recruitment of oxidase components. Activated neutrophils displayed a significant colocalization of KCC3 and early endosomal marker, indicating that KCC3 could be localized on the phagosomes once neutrophils are activated. The NADPH oxidase activity and the phosphorylation level of oxidase component were 50% lower in the neutrophils isolated from KCC3−/− mice than from KCC3+/+ mice. Mortality rate after intraperitoneal challenge with Staphylococcus aureus was higher in KCC3−/− mice, and the bacterial clearance was impaired in the survivors. I conclude that, in activated neutrophil, NADPH oxidase complexes are associated with KCC3 at the plasma membrane and are internalized to form phagosomes, where KCC activity and expression level affect the production of oxidants.

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