The carotid body (CB) is a peripheral chemoreceptor organ that initiates compensatory reflex responses so as to maintain gas homeostasis. Stimuli such as low oxygen (hypoxia) and high CO(2)/H(+) (acid hypercapnia) cause an increase in 'afferent' sensory discharge that is relayed via the carotid sinus nerve (CSN) to the brainstem, resulting in corrective changes in ventilation. A parallel autonomic pathway has been recognized for >40 years as the source of 'efferent' inhibition of the CB sensory discharge and, more recently, nitric oxide (NO) has been identified as the key mediator. This review will examine our current understanding of the role of nNOS-positive autonomic neurons, embedded in 'paraganglia' within the glossopharyngeal (GPN) and CSN nerves, in mediating efferent CB chemoreceptor inhibition. We highlight recent data linking the actions of hypoxia, ACh and ATP to NO synthesis/release from GPN neurons. Finally, we consider the novel hypothesis that pannexin-1 channels present in GPN neurons may play a role in NO signaling during hypoxia.
"This last conclusion was obtained using a modification of the co-culture preparation developed in their laboratory. In this occasion they co-cultured clusters of chemoreceptor cells with autonomic neurons obtained from the glossopharyngeal-CSN and observed that application of ATP or hypoxia to the neurons caused a robust chemoreceptor cell hyperpolarization that was prevented by pre-incubation with NO scavengers and NOS inhibitors; additionally they showed that NO donors, but not ATP itself, was able to hyperpolarize chemoreceptor cells in clusters cultured without the autonomic neurons (see Campanucci et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: When de Castro entered the carotid body (CB) field, the organ was considered to be a small autonomic ganglion, a gland, a glomus or glomerulus, or a paraganglion. In his 1928 paper, de Castro concluded: "In sum, the Glomus caroticum is innervated by centripetal fibers, whose trophic centers are located in the sensory ganglia of the glossopharyngeal, and not by centrifugal [efferent] or secretomotor fibers as is the case for glands; these are precisely the facts which lead to suppose that the Glomus caroticum is a sensory organ." A few pages down, de Castro wrote: "The Glomus represents an organ with multiple receptors furnished with specialized receptor cells like those of other sensory organs [taste buds?]…As a plausible hypothesis we propose that the Glomus caroticum represents a sensory organ, at present the only one in its kind, dedicated to capture certain qualitative variations in the composition of blood, a function that, possibly by a reflex mechanism would have an effect on the functional activity of other organs… Therefore, the sensory fiber would not be directly stimulated by blood, but via the intermediation of the epithelial cells of the organ, which, as their structure suggests, possess a secretory function which would participate in the stimulation of the centripetal fibers." In our article we will recreate the experiments that allowed Fernando de Castro to reach this first conclusion. Also, we will scrutinize the natural endowments and the scientific knowledge that drove de Castro to make the triple hypotheses: the CB as chemoreceptor (variations in blood composition), as a secondary sensory receptor which functioning involves a chemical synapse, and as a center, origin of systemic reflexes. After a brief account of the systemic reflex effects resulting from the CB stimulation, we will complete our article with a general view of the cellular-molecular mechanisms currently thought to be involved in the functioning of this arterial chemoreceptor.
Frontiers in Neuroanatomy 05/2014; 8:25. DOI:10.3389/fnana.2014.00025 · 3.54 Impact Factor
"Panx1 is expressed in the sustentacular (glomus type-II) cells of the carotid body and is thought to amplify an excitatory ATP signal following P2Y 2 receptor activation, leading to increased autonomic ventilation rate (Zhang et al., 2012b). Panx1 is also expressed in the glossopharyngeal nerve (GPN) that transmits signals from the carotid body to the brainstem, and it has been proposed that depolarization induced opening of the channels could release ATP, which drives a positive feedback to coordinate activity among the neurons within the fiber (Campanucci et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: The pannexins (Panxs) are a family of chordate proteins homologous to the invertebrate gap junction forming proteins named innexins. Three distinct Panx paralogs (Panx1, Panx2, and Panx3) are shared among the major vertebrate phyla, but they appear to have suppressed (or even lost) their ability to directly couple adjacent cells. Connecting the intracellular and extracellular compartments is now widely accepted as Panx's primary function, facilitating the passive movement of ions and small molecules along electrochemical gradients. The tissue distribution of the Panxs ranges from pervasive to very restricted, depending on the paralog, and are often cell type-specific and/or developmentally regulated within any given tissue. In recent years, Panxs have been implicated in an assortment of physiological and pathophysiological processes, particularly with respect to ATP signaling and inflammation, and they are now considered to be a major player in extracellular purinergic communication. The following is a comprehensive review of the Panx literature, exploring the historical events leading up to their discovery, outlining our current understanding of their biochemistry, and describing the importance of these proteins in health and disease.
Frontiers in Physiology 02/2014; 5:58. DOI:10.3389/fphys.2014.00058 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Key points Carotid body (CB) chemoreceptor complexes consist of receptor type I cells, intimately associated with glia-like type II cells whose function is poorly understood. We show that type II cells in the rat CB express gap junction-like proteins, pannexin-1 (Panx-1) channels, which form non-selective pores permeable to ions and large molecules such as ATP, a key CB neurotransmitter. Activation of purinergic P2Y2 receptors on type II cells led to a rise in intracellular Ca(2+), and a prolonged membrane depolarization due to opening of Panx-1 channels. In a CB co-culture model, where purinergic P2X2/3-expressing petrosal neurones served as a reporter or biosensor of ATP release, we show that selective activation of P2Y2 receptors on type II cells can lead to ATP release via Panx-1 channels. We propose that type II cells may function as amplifiers of the neurotransmitter ATP during chemotransduction, via the mechanism of ATP-induced ATP release.
The Journal of Physiology 06/2012; 590(Pt 17):4335-50. DOI:10.1113/jphysiol.2012.236265 · 5.04 Impact Factor
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