DeCoursey Thomas E, Cherny Vladimir V
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Harrison, Chicago, IL 60612, USA.
Curr Pharm Des. 2007;13(23):2400-20. doi: 10.2174/138161207781368675.
Voltage-gated proton channels are highly proton selective ion channels that are present in many cells. Although their unitary conductance is 1000 times smaller than that of most ion channels, detection of single-channel currents supports their identification as channels rather than carriers. Proton channels are gated by membrane depolarization, but their absolute voltage dependence is also strongly regulated by the pH gradient, DeltapH (pHo-pHi). A model of this behavior postulates regulatory protonation sites that are alternately accessible to external or internal solutions. Consequently, proton channels open only when the electrochemical gradient is outward, and serve to extrude acid from cells. No "classical" blockers of proton channels that bind to and physically occlude the channel have been identified. A number of weak bases that inhibit proton currents probably act indirectly, perhaps by changing local pH. The best known and most potent inhibitors are polyvalent cations, especially Zn(2+) and Cd(2+). These cations are coordinated at two or more external protonation sites, most likely His residues where they compete with protons and interfere with gating. In phagocytes, proton channels are required to compensate for the electrogenic action of NADPH oxidase. During the "respiratory burst," i.e., when NADPH oxidase is active, proton channels in these cells adopt an "activated" gating mode. Recently, two labs identified a gene that codes for either the proton channel itself or a protein that is essential for proton channel activity. Expression of this protein results in currents with many similarities to the native channel.
电压门控质子通道是存在于许多细胞中的高度质子选择性离子通道。尽管它们的单通道电导比大多数离子通道小1000倍，但单通道电流的检测支持将它们鉴定为通道而非载体。质子通道由膜去极化门控，但其绝对电压依赖性也受到pH梯度ΔpH（pHo-pHi）的强烈调节。这种行为的模型假定了交替可被外部或内部溶液接触的调节性质子化位点。因此，质子通道仅在电化学梯度向外时打开，并用于将酸从细胞中挤出。尚未鉴定出与通道结合并物理阻塞通道的“经典”质子通道阻滞剂。许多抑制质子电流的弱碱可能通过改变局部pH间接起作用。最著名且最有效的抑制剂是多价阳离子，尤其是Zn(2+)和Cd(2+)。这些阳离子在两个或更多外部质子化位点配位，最可能是His残基，它们在那里与质子竞争并干扰门控。在吞噬细胞中，需要质子通道来补偿NADPH氧化酶的生电作用。在“呼吸爆发”期间，即当NADPH氧化酶活跃时，这些细胞中的质子通道采用“激活”门控模式。最近，两个实验室鉴定出一个基因，该基因编码质子通道本身或质子通道活性所必需的蛋白质。该蛋白质的表达产生与天然通道有许多相似之处的电流。
