Modulation of the carotid body sensory discharge by NO: An up-dated hypothesis.
ABSTRACT 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.
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Article: The pannexins: past and present.[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 01/2014; 5:58.
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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 01/2014; 8:25. · 4.06 Impact Factor
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ABSTRACT: Connexins (Cxs) and Pannexins (Panxs) are two non-related protein families, having both the property to form hemichannels at the plasma membrane. There are 21 genes coding for different Cx based proteins and only 3 for Panx. Under physiological conditions, these hemichannels (Cxs and Panxs) present a low open probability, but when open, they allow the release of signaling molecules to the extracellular space. However, under pathological conditions, these hemichannels increase their open probability, inducing important lysis of metabolites, and ionic imbalance, which in turn induce the massive entry of Ca(+2) to the cell. Actually, it is well recognized that Cxs and Panxs based channels play an important role in several diseases and -in many cases- this is associated with an aberrant hemichannel opening. Hemichannel opening and closing are controlled by a plethora of signaling including changes of the voltage plasma membrane, protein-protein interactions, and several posttranslational modifications, including protein cleavage, phosphorylation, glycosylation, hydroxylation and S-nitrosylation, among others. In particular, it has been recently shown that the cellular redox status modulates the opening/closing and permeability of at least Cx43, Cx46, and Panx1 hemichannels. Thus, for example, the gaseous transmitter nitric oxide (NO) can induce the S-nitrosylation of these proteins modulating in turn several of their properties. The reason is that the redox status of a cell is fundamental to set their response to the environment and also plays an important role in several pathologies. In this review, I will discuss how NO and other molecules associated with redox signaling modulate Cxs and Panx hemichannels properties.Frontiers in Physiology 01/2014; 5:80.