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Great men are the true men in whom nature has prospered. They are not extra-ordinary – they are in the true order, what they are ought to be. They reached the summit by doing their jobs in hand with everything they had of energy, enthusiasm and hard work. More importantly, they made every man who came in contact with them feel great. Autar Singh Paintal who passed away on December 21, 2004 in Delhi was indeed such a great man who will be remembered not only for his contributions in Physiology but also for his acts of altruism.

Tandem pore domain K channels can be divided into six subfamilies; TWIK, TASK, TREK, TALK, THIK and TRESK (Patel and Lazdunski, 2004). Its subfamily consists of several subunits. These channel subunits. have 4 transmembrane segments and 2 pore domains. These channels are ubiquitously expressed in the body including central and peripheral nervous systems. Of these channels, TASK (TWIK-related acid-sensitive K channels) family including TASK-1, TASK-2 and TASK-3 are inhibited by extracellular low pH (Lesage, 2003). In addition, it has been shown that TASK-1 and TASK-3 are closed by hypoxia (Hartness et al., 2001; Lewis et al., 2001). Thus, these channels are one of the candidates for oxygen and/or CO/H sensor in chemosensory cells. In the isolated glomus cells of the carotid body, Buckler et al. (2000) found TASK-like current with electrophysiological method and expression of TASK-1 mRNA. On the other hand, TREK (TWIK-related K channels), comprises three subunits, TREK-1, TREK-2 and TRAAK (Kim, 2003). These channels are regulated by polyunsaturated fatty acid, cellular volume, intracellular pH and general anesthetics. It has been suggested that they play an important role in potent neuroprotection (Lesage, 2003). Furthermore, Miller et al. (2003) reported that acute hypoxia occluded human TREK-1 expressed in the HEK293 cells under ischemic and/or acidic conditions. On the contrary, other reports demonstrated that TREK-1 was not oxygen sensitive (Buckler and Honore, 2005; Caley et al., 2005). To discuss the function of the tandem pore domain K channels in the chemosensory organ, we reported that the immunoreactivities for TASK and TREK subfamilies in the carotid body (Yamamoto et al., 2002; Yamamoto and Taniguchi, 2004). Furthermore, no immunoreactivity for TRAAK was found in the paraganglion cells in the sympathetic ganglia (Yamamoto and Taniguchi, 2003). In the present study, therefore, we summarize the immunohistochemical localization of tandem pore domain K channels in the rat paraganglion cells.

Neuroglobin (Ngb), a 151-amino-acid protein with a predicted molecular mass of 17 kD was recently identified as a member of the vertebrate globin family (Burmester and Hankeln, 2004; Mammen et al., 2002). Ngb, is predominantly expressed in nerve cells, particularly in the brain and in the retina (Burmester et al., 2000; Zhu et al., 2002), but is also expressed in other tissues (Burmester and Hankeln, 2004). The protein has three-on-three -helical globin fold and are endowed with a hexa-coordinate heme-Fe atoms, which displays O2 affinities and binds CO (Burmester & Hankeln, 2004).The physiological role of Ngb is not well understood, but it has been proposed that Ngb participates in several processes such as oxygen transport, oxygen storage, and NO detoxification (Burmester and Hankeln, 2004). Ngb as well as hemoglobin is a respiratory protein that reversibly binds gaseous ligands (NO and O2) by means of the Fe-containing porphyrin ring. Ngb is concentrated in neuronal cellular regions that contain mitochondria, and its distribution is correlated with oxygen consumption rates (Pesce et al., 2003).

Physiological responses to hypoxia involve changes in gene expression that are mediated by the transcriptional activator HIF-1. HIF-1 is a heterodimeric transcription factor consisting of two subunits, HIF-1α and HIF-1β (Semenza, 2000; Wang et al., 1995). The expression of HIF-1α protein is closely regulated by oxygen tension in the cell, whereas HIF-1β expression is constitutive and independent of oxygen levels (Kallio et al., 1999; Semenza, 2000; Wang et al., 1995). It has been shown that HIF-1α plays a physiological role in chronic hypoxia (CH). HIF-1α serves as a key controller for the transcriptional regulation of the expression of a spectrum of oxygen-regulated genes, such as erythropoietin, vascular endothelial growth factor (VEGF) and VEGF receptors, for the cellular response to hypoxia in tissues including the carotid body (CB) (Fung, 2003; Glaus et al., 2004; Semenza, 2000; Tipoe and Fung, 2003).

Hypoxia is a crucial physiological stimulus in development and plays a key role in the pathophysiology of cancer, stroke, pulmonary disease, and other major causes of mortality (Iyer et al., 1998). Responses to changes in oxygen concentrations are primarily regulated by hypoxia inducible factors (HIFs). HIFs are heterodimeric transcription factors that regulate a number of adaptive responses to low oxygen tension. They are composed of oxygen-regulatedα - and a constitutive non oxygen-regulatedβ - subunits and are belonged to the basic helix-loop-helix-PAS (bHLH-PAS) superfamily (Bruick, 2003). In mammals, three genes have been shown to encode HIF-α subunits namely HIF-1α, -2α and -3 . The HIF-1α protein is more widely expressed, while its homologs, HIF- 2 /Endothelial PAS domain protein (EPAS-1) (Tian et al., 1997) and HIF-3α (Gu et al., 1998) are tissue and developmental specific in their expression. HIF- 1α is expressed in the brain, heart, lung (Jain et al., 1998) and also in the carotid body (CB) (Baby et al., 2003; Tipoe and Fung, 2003). Whereas HIF-2α is expressed in the endothelial cells of various tissues, such as brain, heart, and liver, and the mRNA is also observed in alveolar epithelial cells in the lung (Ema et al., 1997). The EPAS-1 expression in mice embryo was induced by hypoxia for proper cardiac function (Tian et al., 1998). Furthermore, all the HIF- α subunits have been found in the kidney where diverse functions of the three had been shown. HIF-1α and -2α activate the expression of the HIF-mediated gene such as erythropoietin (EPO), whereas HIF-3α is likely an inhibitor of EPO gene transcription (Hara et al., 2001; Jelkmann, 2004).

The carotid body (CB) is a chemosensory organ which detects a decrease in PaO or pHa and increases spiking levels on the carotid sinus nerve. Chemosensitivity normally increases after birth but this maturation is impaired by post-natal exposure to hyperoxia, resulting in a large reduction in spiking rates during normoxia and hypoxia (Donnelly, 2005) and reduction in carotid type I cell depolarization in response to anoxia (Kim, 2003). Previous studies have indicated that detection of hypoxia or acidity is mediated by modulation of a leak potassium conductance of which TASK-1 and TASK-3 are likely candidates. Accordingly, we hypothesized that post-natal hyperoxia exposure will alter the developmental profile of TASK channels within the carotid body cells.

The carotid body (CB) is a chemosensory organ monitoring blood O level, CO level, and pH. It is known that CB O sensitivity is minimal after birth and increases with age (Bamford, 1999), but the mechanisms of CB development are poorly understood. Previous studies have shown that CB glomus cell background K current is inhibited by acute hypoxia and glomus cell O sensitive background currents increase with age (Kim, 2003). It has been proposed these currents are carried by TASK-like K channels. Therefore, we hypothesized that expression of one or several TASK K channels might change during CB development and contribute to the development of glomus cell oxygen sensitivity.

The carotid bodies are enlarged in the rats exposed to long term hypoxia. In some studies the animals were exposed to hypoxia for relatively short periods, and in other studies for relatively long periods. However, most authors use the term “chronic hypoxia” in their publications. This terminology can cause much confusion. On the other hand, there are no morphological studies of the carotid bodies after the termination of chronic hypoxia except in a few instances (Heath et al., 1973). Recently high altitude training has been used to try to improve some physical conditions. High altitude exercise can help to make clear morphological changes in chemoreceptor organs during acclimatization to hypoxia and during deacclimatization after chronic hypoxia is terminated.

Three types of hypoxia with different levels of carbon dioxide (hypocapnic, isocapnic, and hypercapnic hypoxia) have been called systemic hypoxia (Hirakawa et al., 1997). Recently, the changes in general morphology and in peptidergic innervation in the carotid bodies of rats exposed to systemic hypoxia were examined to evaluate the effect of arterial CO tension (Kusakabe et al., 1998, 2000, 2002). The carotid bodies of the systemic hypoxic rats were found to be enlarged several fold, but the degree of enlargement was different for each (Kusakabe et al., 2003). The mean diameter of the hypercapnic hypoxic carotid bodies were smaller than the hypocapnic and isocapnic hypoxic carotid bodies. The vasculature in the carotid bodies of chronically hypercapnic hypoxic rats was found to be enlarged in comparison with that of normoxic control rats, but the rate of vascular enlargement was smaller than that in hypocapnic and isocapnic hypoxic carotid bodies. This indicates that the morphological changes in the hypoxic carotid bodies may depend on the arterial CO tension. However this hypothesis may be restricted to the carotid bodies in hypoxic conditions. To clarify this we compared the morphological changes and those in the peptidergic innervation between the carotid bodies of the rats exposed to hypercapnic hypoxia and those exposed to normoxic hypercapnia.

Adequate cellular oxygen tension is essential for maintaining a variety of physiological process. Disorder of oxygen delivery eventually leads to the cell dysfunction. Therefore, sensing mechanism of cellular hypoxia is critical. Under hypoxic condition, a lot of protein is induced in mammalian cells for preventing hypoxic stress. Hypoxia inducible factor-1 (HIF-1) is a transcription factor protein that thought to be a one of the key molecule as gatekeeper of cellular hypoxia. HIF-1 regulates the expression of series of genes involved in angiogenesis, oxygen transport and glucose metabolism (1, 2). Most of these gene products utilize for the maintaining O2 homeostasis. HIF-1 is composed of two subunit called HIF-1α and HIF1β (3). In normoxic and hypoxic condition, HIF-1α and HIF1β mRNA are constitutively expressed (4). With regard to the protein level, HIF-1α is hydroxylated at Pro402 and Pro564 by the enzyme designated prolyl hydroxylase domain containing protein (PHD) under normoxia (5, 6). Hydroxylated HIF-1α binds to the von Hippel Lindau protein (pVHL), which is the substrate for ubiquitin ligase complex (7). Therefore, HIF-1α is rapidly degraded under normoxia by the ubiquitin-protease pathway (8, 9, 10). When cells are exposed to hypoxia, HIF-1α protein escapes from this degradation system. Subsequently, accumulated HIF-1α protein translocates to the nucleus, and dimerizes with HIF-1β 11). This heterodimeric protein binds to hypoxia-responsive element (HRE) and induces transcription of downstream genes (12). Thus, transcriptional activity of HIF-1 is primarily dependent on the HIF-1α expression.