A global synergy of ions and voltage?

Abstract

Membrane voltage and intracellular ion concentrations change under various cell states. Changes of both membrane potential and ion concentration can be sensed by the same elements in cell membranes. The calcium-activated potassium channels are a typical example. In hippocampal neurons, action potential waveforms are adapted to repetitive electrical inputs based on calcium-dependent repolarization. This may occur quickly or slowly. In the fast process, the duration of a single action potential becomes shorter. In the slow process, spike frequency and patterns are changed. The fast process is mainly achieved by activation of a class of Kv channel, a BK-type calcium-activated potassium channel. Its activities are regulated by both increase of intracellular calcium and depolarization. In fact, the BK channel has a voltage sensor domain and a cytoplasmic calcium-sensing domain. BK channels are often co-localized with voltage-gated calcium channels and can sense local and rapid calcium increase following opening of a single voltage-gated calcium channel during an action potential. The slower process of modification of neuronal firing depends on another class of potassium channel, the small conductance calcium-activated potassium channel (the SK channel), which binds calmodulin on the intracellular side. In contrast with the BK channel, the SK channel lacks intrinsic voltage dependence. Synergy between membrane voltage change and ions is not restricted to neurons and myocytes. In phagocytes such as the neutrophil or macrophage, reactive oxygen species are produced by the actions of NADPH oxidase. This activity induces remarkable depolarization since superoxide anions are transferred to the external space leaving protons inside. Thus both depolarization and intracellular acidification occur by the oxidase's activity. The voltage-gated proton (Hv) channel serves as an ideal player for cancelling both outcomes of the oxidase activity. The Hv channel is activated by both depolarization and intracellular acidification. Voltage dependence of steady-state open probability measured as the conductance–voltage (G–V) curve is shifted dependent on both intracellular and extracellular pH values. Recently, the molecular correlate of the Hv channel was identified. Knockout mice for the Hv channel exhibit reduced production of superoxide anions in neutrophils, consistent with the view that the Hv channel plays a role in promoting NADPH oxidase activity. More roles of the Hv channel in other cell types are also emerging. A study of knockout mice for the Hv channel led to the identification of unexpected roles in the signals of antibody production in B-lymphocytes. Another surprise was its presence and potential role in human sperm. Many ion channel species are expressed in sperm, but how ion channels contribute to sperm physiology, such as motility, has remained unknown. Patch clamping of sperm has now brought about a revolution in this field. This series of reviews covers three ion channel topics that explore the sites of synergy between voltage and ions. Jianmin Cui reviews recent findings of the structure–function relationship of the BK-type calcium-activated potassium channel (Cui, 2010). The interaction between S4, a key transmembrane segment of the voltage sensor domain, and the cytoplasmic metal ion-binding sites is one focus and the recently resolved X-ray structure of the cytoplasmic domain for calcium sensing is also discussed. Demaurex & Chemaly (2010) review the historical background of the Hv channel in leukocytes and recent molecular studies. Finally, Lishko & Kirichok (2010) review the recent discovery of the Hv channel in human sperm and its functional coupling with the CatSper channel, another class of voltage sensor containing channel that operates as an alkalization-activated calcium channel.