Two-pore domain K+ (K2P) stations are involved in a variety of physiological processes by virtue of their high basal activity and sensitivity to various biological stimuli. body Rabbit Polyclonal to OR1A1. chemoreceptor cells and adrenal medullary/cortical cells. Studies show that stimuli such as hypoxia and acidosis cause cell depolarization and transmitter/hormone secretion by inhibition of TASK or TREK. Subsequent elevation of [Ca2+]i produced by opening of voltage-dependent Ca2+ channels then activates a Na+-permeable cation channel presumably to help sustain the depolarization and [Ca2+]i. Agonists such as angiotensin II may elevate [Ca2+]i via multiple mechanisms involving both inhibition of TASK/TREK and Ca2+ release from internal stores to cause aldosterone secretion. Thus inhibition of resting (background) K+ channels and subsequent activation of voltage-gated Ca2+ channels and Na+-permeable non-selective cation channels may be a common ionic mechanism that lead to hormone and transmitter secretion. but not in dispersed cells. Such [Ca2+]i oscillations could account for the basal release of catecholamines in normoxia unrelated to any effect on TASK activity. Autocrine actions of transmitters such as ATP and adenosine may also assist in spontaneous fluctuations in Em and [Ca2+]i [59]. Clearly more definitive studies are needed to understand the Senkyunolide I relative contributions Senkyunolide I of TASK and BK to hypoxia-induced depolarization rise in [Ca2+]i and transmitter secretion and in vivo. The effect of hypoxia on BK also needs to be reevaluated as most studies have not tested this under strict physiological conditions in intact cells. Studies in mice lacking the TASK gene The role of TASK in hypoxia-induced transmitter secretion has been studied in TASK knockout mice but the findings from these studies are unexpected and interpretation is somewhat difficult. In the first study the hypoxia- and hypercapnia-induced increase in ventilation was impaired in TASK1?/? and TASK1/3?/? mice (double Senkyunolide I knockout) but not in TASK3?/? mice [58]. The carotid sinus nerve activity a measure of transmitter secretion from the carotid body was also similarly reduced in TASK1?/? and TASK1/3?/? mice but not in TASK3?/? mice leading the authors to conclude that TASK1 is the important hypoxia-sensitive channel in mice. If TASK-1/3 is the major background channel why do TASK1?/? and TASK3?/? mice show such different hypoxic responses? One possible explanation is that TASK1?/? and TASK3?/? mice express markedly different degrees of Job3 and Job1 and therefore influence the amount from the hypoxic response respectively. In another research the relaxing Em of glomus cells assessed by perforated patch technique was ~3 and ~5 mV even more depolarized in Job1?/? and Job1/3?/? mice than outrageous type mice whose relaxing Em was respectively ?57 mV [47]. Oddly enough catecholamine secretion in response to hypoxia was taken care of Senkyunolide I in TASK1/3?/? mice even after blockade of BK channels. In support of Senkyunolide I these findings [Ca2+] responses to hypoxia and cyanide were comparable in TASK knockout and wild type mice regardless of which TASK isoform was deleted [60]. These studies suggest that TASK has a minor role in pheripheral chemoreception. However it is usually difficult to reconcile the findings observed in TASK?/? mice with what we know about TASK1/3 in glomus cells which is that TASK1/3 is the major background K+ channel and strongly inhibited by hypoxia [10 35 Could it be that the loss of TASK1/3 is usually somehow compensated by a change in chemoreceptive mechanism in the carotid body as well as in other respiratory areas of the brainstem? If so there must be other ion channels that are open near the resting Em and sensitive to inhibition by hypoxia but such channels have not yet been reported. It would be interesting to determine which non-TASK ion channels are expressed in TASK1/3?/? mice and which of these ion channels are sensitive to hypoxia. Central chemoreception as judged by the ventilatory sensitivity to elevated pCO2 was found to be unchanged in TASK1/3?/? mice compared to wild type mice [43]. Therefore the remodeling may be specific to the peripheral chemoreceptors. To resolve these important issues a conditional knockout system with drug-controlled transcriptional activation where transcription of a gene can be reversibly turned on or off would be preferred. This would limit the extent of remodeling of the O2 sensing mechanism and allow.