br Some Gardos channel perplexities While much is known

Some Gardos channel perplexities While much is known about the Gardos channel (inside Ca2+-activated K+ channel) and it's characteristics in human red blood PF-00562271 (e.g. [18,19]), there are a number of intriguing and unexplained phenomena that are in much need of study. One is that activation of the channel by Ca2+ or Pb2+ [20] displays under certain circumstances all-or-none kinetics. All-or-none characteristics are not new to red cells for it is known that in hypotonic hemolysis, under various conditions, hemoglobin either fails to escape from the cells or does so completely attaining diffusion equilibrium [21]. All-or-none loss of K+ is illustrated in Fig. 1 (Fig. 7 in ref. [20]) for the Gardos channel where intact red cells have been exposed to varying concentrations of Pb2+. Similar results were also seen in resealed ghosts containing different concentrations of Ca2+ (Fig. 9 in [20]). In the experiments with Pb2+ the cells were shown, by density separation, to either retain their original K+ content or to lose their K+ to equilibrium. While the mechanism is not known, this type result implies that different channels in the membrane have different affinities for the divalent ligands (see [20]). Another unusual if not unique characteristic of the Gardos channel is its sensitivity to temperature [22]. Grygorczyk showed that in excised inside-out patches of human red cells that while the single channel conductance did not change, the open probability increased (reversibly) from about 0.1 at 37 °C to about 0.6 at 20 °C. The K+ flux via the Gardos channel was also shown to increase as the temperature was lowered from 35 °C to 25 °C [18]. An explanation for this unusual if not unique sensitivity to temperature is needed. Other unexplained properties of the Gardos channel include the effect of external K+. Activation of the channel has an obligatory requirement for external K+ [23]. Incubation of Ca2+-loaded resealed ghosts in the absence of external K+ renders them unresponsive to the subsequent exposure to external K+. While external protons have been shown to compete with external K+, protons cannot activate the Gardos channel in the absence of external K+. The mechanism of action of substances that either stimulate the Gardos channel, such as prostaglandin E2 [24] or inhibit, such as charybdotoxin or clotrimazole, are also unknown. Perhaps when the atomic structure of the Gardos channel protein has been solved, insight into the ways the effects discussed above may be revealed.
Life at high altitude The physiology associated with adaptations to unusual environments is never more remarkable than those that provide the ability of the Bar-headed Goose (Anser indicus) and the Andean goose (Chloephaga melanoptera) to fly at very high altitudes. The former goose flies over the Himalayas while the latter goose flies over the Andes mountain ranges. Each species has, for instance, lung and muscle adaptations but none more curious than the mutations that have occurred in their respective hemoglobins (Hb). The Hbs in both species have changes that result in an increased affinity for O2 which increases its utilization efficiency [25]. It is remarkable that the mutations in Hb of the Bar-headed goose are somewhat different than those in the Andean goose: namely, for instance, in the former the inter-subunit contact is Ala-α119 and Leu-ß55 while in the latter the contact is between Pro-α119 and Ser-ß55. Nevertheless the αß interaction in the two Hbs lies adjacent to each other on the different polypeptide chains. Similar interactions have been extensively studied in other types of birds that also show impressive instances of convergent evolution [26,27]. In addition to the geese, Rippon's griffon, an African vulture, that evidently can fly as high as 11 km, is said to have four types of Hbs, rather than the usual one or two of low flying birds, that provide O2 loading and unloading functions over a wide range of tensions (see: [28], p. 112). Yaks, also living at high altitude, are said to have four types of HBs in their cells [29].