在許多組織或是可興奮的細胞（excitable cell）都有維持細胞內及細胞外pH值恆定的機制。而細胞內及細胞外pH值的改變對許多細胞功能來說是一個很重要的調節因子；因為許多催化酵素或是組成離子通道的蛋白都受pH的改變而影響。近二十年來，隨著測量細胞內pH值技術的發展，使我們對細胞內pH值的調控有更深入的瞭解。
在生理或病理狀態下，我們常見神經系統細胞內及細胞外pH值的改變，此等pH值改變對神經功能之影響卻仍不甚清楚。在論文的第一部分，我們探討了細胞內及細胞外pH值的改變對胚胎期神經末梢釋放ACh的調節。當我們在與神經形成突觸的肌細胞形成whole-cell recording並將膜電位箝制在-60mV時，可記錄到突觸前神經釋放的ACh在肌細胞所引起的內向電流。在本實驗中我們以氯化銨（NH4Cl）來鹼化細胞，而細胞內的pH值則是以對氫離子（H+）敏感的BCECF來測定。15 mM的NH4Cl可造成約0.77個pH單位的鹼化，但SSC frequency僅稍微減少一些；而洗掉NH4Cl造成細胞內0.85到1.0個pH單位的反彈性酸化現象（rebound acidificaiton）卻明顯地促進SSC frequency。另一種酸化細胞的方法是以弱有機酸如Na acetate或Na propionate完全取代Ringer溶液中的NaCl也可以造成細胞內的酸化，我們並將細胞外溶液之pH值滴定至6.6以增加acetate或propionate的uncharged form，使之進入細胞的量增加而促進細胞酸化的程度。當細胞外pH 7.6的Ringer溶液被置換成pH 6.6 或pH 8.6的Ringer溶液時，對細胞內的pH並無顯著影響，分別為0.14及0.11個pH單位。但以Na acetate或Na propionate取代pH 6.6 Ringer溶液中的NaCl約造成細胞內1.2~1.6個pH單位的酸化，並且明顯地增加SSC frequency；但較強的有機酸如Na isethionate、Na methylsulfate及Na glucuronate則因charged form分子較多無法通過細胞膜，因而酸化細胞的效果不明顯，對SSC frequency亦無顯著之影響。然而細胞內酸化對電刺激引發的ACh釋放（evoked ACh release）卻有不同的調節作用。細胞內鹼化促進但細胞內酸化卻抑制evoked ACh的釋放。由於鈣離子（Ca2+）在神經傳遞物質的釋放過程中扮演著重要的調節角色，因此我們利用Ca2+的探測劑：Fura-2 AM繼續探討細胞內酸化對細胞內Ca2+的影響。以Na acetate取代NaCl酸化細胞會增加細胞外Ca2+進入細胞內，同時也促進Ca2+從細胞內的Ca2+儲存池（Ca2+ pool）釋放出來，因而導致細胞內Ca2+濃度的增加。而高鉀溶液增加[Ca2+]i的作用在細胞內酸化的情況下則是被抑制。因此我們得到的結論是：在胚胎期運動神經，細胞內酸化促進自發性ACh release，卻抑制電刺激所引發的ACh release，但細胞外酸化對此二者的作用則均不明顯。至於細胞外鹼化則稍微減少自發性ACh release，但卻稍稍促進evoked-ACh release。
已知NMDA及non-NMDA受體與ACh受體一起存在於Xenopus細胞培養中的運動神經末梢，glutamate可經由此突觸前NMDA及non-NMDA受體增加細胞內Ca2+濃度而增強自發性ACh釋放。而在哺乳類動物的中樞神經，興奮性的glutamate在生理及病理上都扮演著重要的調節角色。在生理上，胚胎期神經的分化發育、突觸形成及成熟個體的學習、記憶如長期增益現象（LTP）均與glutamate受體有密切關係。在病理上，癲癇、中風及神經萎縮性病變如退化性老年癡呆症（Alzheimer''s disease），亨庭頓氏手足舞蹈症（Huntington''s desease）及側索硬化性肌萎縮症（amyotrophic lateral sclerosis）的成因也與glutamate受體有關。因此我們繼續探討細胞內、外pH值的改變對NMDA以及non-NMDA受體性質的影響。此外，由於有報告指出抑制性的神經傳遞物質- GABA在胚胎發育的早期亦扮演著興奮性的角色，因此我們也將探討細胞內、外pH值改變對GABA受體的影響。
實驗中我們分三方面來評估細胞內、外pH值改變對Xenopus運動神經NMDA受體性質的影響。分別是1）NMDA受體促進突觸前神經末梢自發性ACh釋放之作用，2）NMDA增加細胞內Ca2+的作用，以及3）NMDA在神經元細胞體上直接引發的電流反應。我們同樣以Na acetate或Na propionate完全取代Ringer溶液中的NaCl，但細胞外pH仍維持在7.6。以此取代方法可造成細胞內0.2至0.4個pH單位的酸化。我們發現當以pH 6.6 Ringer溶液酸化細胞外時會抑制NMDA增加SSC frequency的作用，而以Na acetate取代NaCl酸化細胞內時則促進NMDA的作用；另一方面，細胞外鹼化（pH 8.6 Ringer溶液）促進，但以NH4Cl使細胞內鹼化則對NMDA的作用沒有明顯的影響。由於NMDA受體是一個可容Ca2+通過的離子管道，因此藉由測量細胞內Ca2+濃度的變化也可以瞭解細胞內外pH值的改變對NMDA受體的影響。NMDA增加[Ca2+]i的作用可被細胞外鹼化及細胞內酸化促進，而細胞外酸化則抑制之；至於細胞內鹼化則不影響NMDA的作用。更直接的證據就是我們在神經細胞體上灌流NMDA所引發的電流也被細胞外鹼化及細胞內酸化促進，但卻被細胞外酸化所抑制；細胞內鹼化則依然不影響NMDA所引發的電流。
至於non-NMDA受體，當細胞外鹼化至pH 8.6時促進AMPA及kainate受體所引起的電流。以NH4Cl造成的細胞內鹼化則只促進kainate受體所引起的電流；而細胞內及細胞外酸化對AMPA及kainate受體均無顯著的影響。與NMDA受體相較，AMPA及kainate受體對細胞內、外pH值改變的敏感度較低，也因此NMDA受體在興奮性傳遞物質所造成的神經毒性上扮演著較為重要的角色。
而在GABA受體方面，當我們以gramicidin形成perforated patch而不改變細胞內Cl-濃度的情況下，若將細胞膜箝制在-60mV、並灌流GABA時，可在神經細胞體記錄到一個內向的電流；這表示GABA在胚胎發育早期扮演著去極化的興奮性角色。由於GABA受體是一個容Cl-通透的離子管道，以Na acetate取代NaCl而酸化細胞的同時也改變了細胞外氯離子的濃度，進而影響GABA受體的平衡電位（equilibrium potential），因此我們以洗去NH4Cl之後產生的rebound acidification來探討細胞內酸化對GABA及muscimol-induced currents的影響。實驗結果顯示：當細胞外鹼化及細胞內酸化時明顯地促進GABA及muscimol-induced currents；反之，細胞外酸化及細胞內鹼化對GABA及muscimol-induced currents則無顯著作用。
綜合以上對NMDA、AMPA、kainate及GABA受體的實驗結果顯示：細胞外鹼化及細胞內酸化促進興奮性GABAA受體的活性，與NMDA受體活性受調節的方向一致；但GABAA受體與NMDA受體對細胞外酸化的敏感度卻大不相同。相較於NMDA受體對細胞外酸化的敏感性，細胞外pH 7.6降到6.6的酸化程度對於GABAA、AMPA及kainate受體的影響都不顯著。然而，細胞外鹼化都可促進NMDA、AMPA、kainate及GABAA受體的活性。此結果顯示這些ligand-gated受體的extracellular domain可能有部分的相似性。

It has been commonly assumed that both extracellular pH (pHo) and intracellular pH (pHi) in various excitable cells and tissues are well regulated by homeostatic mechanisms. Changes in pHo and pHi tend to exert profound effects on the properties of cells, because enzymes and ion channels are clearly affected by changes in pH. In the last two decades, however, several techniques for measuring pHi have evolved to study how pHi is regulated.
Both intra- and extralcellular pH will be changed under physiological or pathological conditions. However, the functions of such pHo and pHi changes are still unknown. We study the effects of intracellular pH changes on the ACh release and cytoplasmic Ca2+ concentration at developing motoneurons in Xenopus nerve-muscle co-cultures in the first part of the article. Spontaneous and evoked ACh release of motoneurons was monitored by using whole cell voltage-clamped myocytes (Vh=-60 mV). Intracellular alkalinization with 15 mM NH4Cl slightly reduced the frequency of spontaneous synaptic currents (SSCs). However, cytosolic acidification following withdrawal of extracellular NH4Cl caused a marked and transient increase in spontaneous ACh release. Another method of cytosolic acidification was used in which NaCl in Ringer solution was replaced with weak organic acids. The increase in spontaneous ACh release parallel the level of intracellular acidification resulting from addition of these organic acids. Acetate and propionate but not isethionate, methylsulfate and glucuronate caused an incerease in intracelluar pH and a marked increase in spontaneous ACh release. Impulse-evoked ACh release was slightly augmented by intracellular alkalinization and inhibited by cytosolic acidification. Cytosolic acidification was accompanied by an elevation in the cytoplasmic Ca2+ concentration ([Ca2+]i), resulting from both external Ca2+ influx and intracellular Ca2+ mobilization. In contrast, the increase in [Ca2+]i induced by high K+ was inhibited by cytosolic acidification. We conclude that cytosolic acidification regulates spontaneous and evoked ACh release differentially in Xenopus motoneurons, increasing spontaneous ACh release but inhibiting evoked ACh release.
We previously found that glutamate, which is also reported to be co-released from some cholinergic nerve terminals, markedly increased the frequency of spontaneous synaptic currents at embryonic neuromuscular synapses via the activation of NMDA and non-NMDA receptors. L-Glutamate also plays an important role as an excitatory synaptic neurotransmitter in the mammalian CNS. Activation of glutamate receptors serve many functions in neuronal development, synaptic plasticity, and acquisition of memory. They also contribute to the pathology of epilepsy, stroke, and neurodegenerative disorders such as Alzheimer''s disease, amyotrophic lateral sclerosis, and Huntington''s disease. In the second part, we further investigate the effects of both external and intracellular pH changes on the functional responses of presynaptic NMDA receptors. Local perfusion of NMDA at synaptic regions increased the SSC frequency via the activation of presynaptic NMDA receptors. A decrease in pHo from 7.6 to 6.6 reduced NMDA responses to 23% of the control, and an increase in pHo from 7.6 to 8.6 potentiated the NMDA responses in increasing SSC frequency. The effect of NMDA on intracellular Ca2+ concentration ([Ca2+]i) was also affected by pHo changes: external acidification inhibited and alkalinization potentiated [Ca2+]i increases induced by NMDA. Intracellular pH changes of single soma were measured by ratio fluorometric method using 2,7-bis (carboxyethyl)-5,6-carboxyflurescein (BCECF). Cytosolic acidification was used in which NaCl in Ringer solution was replaced with weak organic acids. Acetate and propionate but not methylsulfate substitution caused intracellular acidification and potentiated NMDA responses in increasing SSC frequency, intracellular free Ca2+, and NMDA-induced currents. On the other hand, cytosolic alkalinization with NH4Cl did not significantly affect these NMDA responses. These results suggest that the functions of NMDA receptors are modulated by both pHo and pHi changes, which may occur in some physiological or pathological conditions.
Local perfusion of AMPA and kainate also generated inward currents in the neuronal soma, which were also potentiated by extracellular alkalinization to pH 8.6 and not affected by external acidification to pH 6.6. However, cytosolic acidification by replacing NaCl in Ringer solution with weak organic acid sodium acetate did not affect kainate- and AMPA-induced currents, whereas, intracellular alkalinization enhanced kainate-induced current by 20%. Compared with NMDA receptors, AMPA and kainate receptors are much less sensitive to the modulation by both external and cytosolic pH changes. Therefore, NMDA receptor appears to play a prominent role in excitatory amino acid-mediated neurotoxicity.
g-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian CNS. However, GABAergic synaptic transmission appears earlier than that of glutamatergic transmission in the early development of the CNS. Thus, GABA acting at GABAA receptors depolarizes and excites immature neurons in the mammalian CNS and developing motoneuron. We also investigated the effects of cytosolic and extracellular pH changes on GABA-induced currents by using perforated whole-cell recordings.
Local application of GABA and muscimol generated inward currents and depolarization in the neuronal soma. GABA- and muscimol-induced currents were enhanced by ~20% when the pHo was increased from pH 7.6 to 8.6 but not significantly affected by external acidification from pH 7.6 to 6.6. Cytosolic alkalinization with NH4Cl did not significantly affect GABA- and muscimol-induced currents. However, withdrawal of NH4Cl from bathing solution caused rebound acidification of cytosolic pH and increased GABA and muscimol-induced currents.
Our data suggest that GABA-mediated currents were affected by external alkalinization and cytosolic acidification, which are in parallel to that of NMDA responses. In contrary, GABA responses are more resistant to external acidification, which is quite different from that of NMDA responses. Changes in H+ within the range of pH 6.6 to 7.6, both AMPA and kainate receptors were also not affected by acidic pHo. In view of our data, it seems that GABA, AMPA and kainate receptors are less sensitive to external acidic shifts than NMDA receptors. However, NMDA, AMPA, kainate and GABA receptors are all potentiated by external alkalinization from pH 7.6 to 8.6. This result suggests that these ligand-gated receptors might show some similarity in extracellular domain.

封面
目錄
縮寫表
中文摘要
英文摘要
第一章.緒論
一)pH值改變對細胞功能的影響
二)L-Glutamate受體的生理角色、特性及其分類
三)GABA受體之生理角色、特性及其分類
第二章.細胞內酸化對胚胎期運動神經末梢ACh釋放之調簡
Regulation of acetylcholine release by intracellular acidification of developingmotoneurons in Xenopus cell cultures
第三章.細胞內細胞外pH值的改變對胚胎期運動神經末梢NMDA受體反應性之調節
Regulation of presynaptic NMDA responses by external and intracellular pH changes at developing neuromuscular synapses
第四章.細胞內及細胞外pH值的改變對胚胎期運動神經GABA及non-NMDA受體性值之調節
Regulation of GABAand non-NMDA glutamate receptors by cytosolic and extracelluar pH changes
第五章.結論及未來展望
著作
其他

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