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• W2070981796 abstract "Its now 25 years since the publication of a seminal study within the field of carotid body chemotransduction (López-Barneo et al. 1988). For decades prior to this publication, researchers were building an increasingly detailed understanding of the ways in which the carotid body responded to hypoxia and several other stimuli, and how this translated, via afferent fibres of the carotid sinus nerve (CSN), into cardiorespiratory responses (reviewed by Kumar & Prabhakar, 2012). However, the fundamental physiological question of how the carotid body sensed hypoxia and translated this into increased chemosensory activity remained largely unanswered until the publication by López-Barneo et al. (1988). These authors demonstrated that isolated type I cells from rabbit carotid bodies expressed K+ channels that were selectively inhibited by acute hypoxia. This finding, rapidly supported by studies of other groups (reviewed by Peers et al. 2010), initiated the development of the ‘membrane hypothesis’ for hypoxic chemotransduction. This hypothesis proposes that hypoxia, by inhibiting K+ channels in type I cells, causes their depolarization, triggering voltage-gated Ca2+ entry. The rise of [Ca2+]i subsequently permits release of excitatory neurotransmitters, which increase the firing frequency of afferent chemosensory fibres of the CSN. Over the subsequent two decades, numerous studies have tested the membrane hypothesis, and yet some fundamental issues remain to be resolved fully, not least of which is a full understanding of the molecular mechanisms coupling hypoxia to altered K+ channel activity. During this period, a number of controversies have also arisen within the field. Much debate has surrounded the molecular identity of the O2-sensitive K+ channels of type I cells, the neurotransmitters involved in the hypoxic response and the sensitivity of the carotid body to hypoglycaemia (Kumar & Prabhakar, 2012), among other factors. Lack of consensus is attributable, for example, to the existence of more than one O2-sensitive K+ channel being expressed by any given type I cell, but perhaps more importantly because of the diverse range of preparations that have been employed to date. Thus, type I cells have been isolated from rabbits, rats, mice and cats, and animals of widely differing ages have been used for such isolations. Furthermore, cells have either been used for study on the day of isolation (which may or may not have allowed sufficient time to recover from the potential stress of isolation) or have been maintained in primary culture for variable periods of time, raising the possibility of altered protein expression (e.g. K+ channels) and/or altered stimulus sensitivity (e.g. hypoglycaemia) occurring as a consequence of being maintained in vitro. Resolution of these discrepancies is important not only to satisfy the natural curiosity of the physiologist, but also to take our knowledge of carotid body function into the translational arena. The organ is, for example, pivotal in the ventilatory changes associated with exercise, pregnancy and adaptation to high altitude, and is of clinical importance in the pathophysiology of several very widespread diseases, such as sleep apnoea, congestive heart failure, hypertension (Kumar & Prabhakar, 2012) and metabolic diseases (Ribeiro et al. 2013). With a more complete understanding of how the carotid body functions, molecular targets can be identified, which may be clinically useful. Therefore, to use the information gained over the past 25 years for clinical benefit, we need to know whether the cellular properties of the carotid body hold true in the human and, if so, what the exact mechanisms involved in chemotransduction are in the human carotid body. The paper by Ortega-Sáenz et al. (2013), published in this issue of The Journal of Physiology, is an important first step along this path. These authors have, for the first time, taken functional carotid bodies from cadavers within 3 h of cardiac arrest (following removal of other organs for donation) and confirmed that cellular properties of the human carotid body are similar to those described for lower mammals, with the carotid body parenchyma organized into clusters of type I cells enveloped by type II cells. Interestingly, they observed that a surprisingly small fraction of the putative type I cells expressed tyrosine hydroxylase (often used as a marker of type I cells), but this could be attributable to various pharmacological interventions made immediately prior to death. They also detected abundant Glial cell-derived neurotrophic factor (GDNF) expression, which is primarily found in type I cells, and provided evidence of tissue plasticity, with the presence of progenitor cells (most probably type II cells) and the ability to grow neurospheres, as this group showed previously when identifying type II cells as stem cells capable of generating new type I cells within the carotid body (Pardal et al. 2007). Perhaps more importantly, this study demonstrates that human type I cells exhibit voltage-gated Na+, K+ and Ca2+ currents and respond to acute hypoxia in a manner consistent with the membrane hypothesis, i.e. hypoxia causes a rise in [Ca2+]i and neurotransmitter release, this being inhibited by blocking voltage-gated Ca2+ entry. Also, evidence for direct glucose sensing by type I cells was found, although this is a non-consensual topic, as discussed by the authors. This notwithstanding, the paper by Ortega-Sáenz et al. is a landmark study, providing the first, preliminary data that the membrane hypothesis is alive and well in the human carotid body. As well as coming as a relief to those who have studied O2 sensing by type I cells in other species, the work lays the foundation for probing the molecular identity of each component of this process, and so, hopefully, informing the development of new approaches to modulating this fundamental process of O2 sensing for clinical benefit." @default.
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• W2070981796 title "Carotid body chemotransduction gets the human touch" @default.
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