One way to approach this unifying

One way to approach this unifying hypothesis will be to compare the effects of the PBR/VDAC ligands on these processes. Recent studies have demonstrated that the three ligands of peripheral-type benzodiazepine receptor, i.e. PK 11195, Ro5-4864 and diazepam reduce membrane transport and conductance in P. falciparum-infected erythrocytes and that these ligands also inhibit in vitro intraerythrocytic growth of P. falciparum-infected erythrocytes. In conclusion, the human red blood cell is endowed with powerful tools allowing fast variations of volume, acid–base and electrolytes status, thereby modulating its respiratory function, and it would thus be overly simplistic to consider ionic channels as mere relics. Even though the state of “resting cell” is the most frequent in ex vivo conditions, it is most likely that the RBC's life is much more hectic. With a mean cardiac output of 5L/min and a volume of blood of 5L, the red cell of healthy adult human must perform a round trip every single minute. This means that a RBC has to squeeze approximately 160,000 times (in absence of muscular exercise) through pulmonary and tissue TC-I 2000 with a diameter lower than its own. There is increasing evidence that, in case of excessive tissue demand, a signalling pathway is activated resulting in the release of ATP acting in a paracrine fashion to increase vascular calibre. The permeability pathways involved in this process are not well defined but it is reasonable to consider that calcium entry through PCa plus Gardos channel activation plus PBR/VDAC activation in either of its two modes (cationic or anionic) provide the cell with a fantastic machinery. In addition to matching oxygen delivery with local need, these pathways give the RBC the potential to in situ adapt its own membrane deformability and volume. The coexistence of Gardos channel and VDAC, enabling induction of inverse volume variations, combined with efficient Ca2+-ATPase and Na+/K+-ATPase constitute much more an advantage than a threat for RBC homeostasis.
Acknowledgments We thank Poul Bennekou and Peter David for helpful discussions and for reading the manuscript. EG is supported by ANR (-08-MIEN-031-02).
Introduction Ca-activated K+ channels (KCa) are a type of K+ channels widely expressed in various tissues including epithelia, smooth muscle, neuron, and endothelium and are involved in a variety of cellular functions including excitability, smooth muscle contractility, and Ca homeostasis. Based on the single channel conductance, KCa channels are classified into three subtypes: big conductance (BKCa, ~200–300pS), intermediate conductance (IKCa, ~32–39pS), and small conductance (SKCa; SK1, SK2, and SK3, ~4–14pS) KCa channels. Due to their different electrophysiological properties and tissue distribution, the three types of KCa channels have distinct physiological or pathological functions. In this chapter, we summarize the physiological and pathological role of these three types of KCa channels in cardiovascular system and put forward the possibility of KCa channels as potential target for cardiovascular diseases.
Big Conductance Ca-Activated K+ Channel (BKCa) channels are channel complexes which have been well described (Zhang & Yan, 2014), and the schematic structure of BKCa channel complexes was shown in Fig. 1. BKCa channel complexes compose of either homotetramers of the pore-forming and calcium- and voltage-sensing ɑ subunit (BKɑ, which is encoded by KCNMA1 gene) alone or BKɑ together with tissue-specific auxiliary β subunits and γ subunits. Four different β subunits (β1–β4) have been cloned and identified in mammals. The leucine-rich repeat-containing proteins (LRRC), LRRC26, LRRC52, LRRC55, and LRRC38, were named as γ1, γ2, γ3, and γ4, respectively, according to their capabilities to modify the voltage dependence of BK channel activation (Yan & Aldrich, 2012). Compared with IKCa and SKCa channels, the typical property of BKCa channels is that their activation is dependent on both voltage and intracellular Ca. In addition, BKCa channel activity is regulated by numerous mechanisms, including the auxiliary β and γ subunits, arachidonic acids, NO, protein kinase A, C, G, and CaMKII, thus, it is undoubted that BKCa channels play an important role in regulating the function of cardiovascular system.