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Hot Topic Review |
1 Department of Physiology & Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 440109, USA
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Abstract |
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(Received 10 August 2005;
accepted after revision 5 October 2005; first published online 20 October 2005)
Corresponding author N. R. Prabhakar: Department of Physiology & Biophysics, School of Medicine, Case Western Reserve University, 1090 Euclid Avenue, Cleveland, OH 44019, USA. Email: nrp{at}case.edu
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Introduction |
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Much attention has been focused on how the carotid body senses changes in arterial PO2 and converts the hypoxic stimulus to afferent nerve activation. The currently accepted view is that sensing of hypoxia in the carotid body involves an initial transduction step and subsequent activation of the afferent nerve ending (sensory transmission). A number of putative O2 sensors have been proposed for the transduction process. Available evidence indicates that neurotransmitters are critical for afferent nerve activation by hypoxia. Indeed, the carotid body, despite its small size (weight, a few micrograms) expresses as many types of neurotransmitters as the brain, some being excitatory and others inhibitory. A number of reviews have been written focusing on mechanisms of O2 sensing in the carotid body (Gonzalez et al. 1994; Prabhakar, 2000; Lopez-Barneo et al. 2001), neurotransmitters in afferent nerve activation (Prabhakar, 1994; Gonzalez et al. 1994; Iturriaga & Alcayaga, 2004; Nurse, 2005), adaptations to chronic hypoxia (Bisgard, 2000; Prabhakar & Jacono, 2005) and the role of chemoreceptors in health and disease (Prabhakar & Peng, 2004). Because of the space constraints, these topics will not be discussed in this brief review, rather I will focus on the following issues: (a) whether the transduction involves single or multiple O2 sensors; (b) the identity of the excitatory transmitter(s) that mediate the afferent nerve activation by hypoxia; and (c) whether inhibitory transmitters have any functional role.
Unique features of O2 sensing by the carotid body
Almost all mammalian cells respond to hypoxia. Examples of cellular responses to hypoxia include transcription factor activation and alterations in second messengers, (Semenza, 2000). However, the following features distinguish the O2 sensing by the carotid body from other tissues. For instance, even a modest decrease in arterial PO2 from 
100–80 mmHg is enough to evoke afferent nerve activation in the carotid body. On the other hand, more severe hypoxia (usually PO2 values much below 40 mmHg) is needed to evoke cellular responses. Afferent nerve activation by hypoxia occurs within seconds, whereas cellular responses are slow in onset and require prolonged exposures to hypoxia (minutes to hours). The increased afferent nerve activation of the carotid body is maintained during the entire period of hypoxia with little or no adaptation (Kou et al. 1991). In some spices (e.g. goats), the sensory activity may even increase progressively during sustained hypoxia lasting several hours (Nielson et al. 1988). The remarkable sensitivity, the speed with which it responds, and the little or no adaptation to hypoxia makes the carotid body a unique sensory receptor for monitoring changes in the arterial blood PO2.
Site(s) of O2 sensing in the carotid body
The chemoreceptor tissue is composed of two cell types: type I and type II. Type I cells (also called glomus cells) are of neural crest origin and express a variety of neurotransmitters. Type II cells (also called sustentacular cells) resemble glial cells and are supporting cells. Type I cells form synaptic contacts with the afferent nerve endings whose cell bodies lie in the petrosal ganglion. Much of the available evidence suggests that the type I cells are the initial sites of O2 sensing and that they work in concert with the opposing afferent nerve ending as a ‘sensory unit’.
Measures of O2 sensing in the carotid body
Three types of recordings are currently being used as measures of O2 sensing in the carotid body: (a) recording of action potentials from the sinus nerve; (b) release of transmitters (e.g. dopamine); and (c) ion channel activity in type I cells. The sensory activity can be monitored both in vivo and in ex vivo carotid bodies, and the advantage of the latter preparation is that it allows the monitoring of O2 sensing of the tissue without the confounding effects from changes in blood pressure and/or circulating hormones. The response of the sensory activity to PO2 resembles ventilatory stimulation by hypoxia. Because stimulation of breathing is one of the functional consequences of carotid body activation, hypoxia-evoked afferent nerve activation has long been regarded as a ‘standard’ measure of O2 sensing by the carotid body.
The carotid body releases a variety of neurotransmitters in response to hypoxia. Therefore some investigators monitor transmitter release, especially the release of dopamine either from ex vivo carotid bodies or from carotid body slices as a measure of O2 sensitivity (Gonzalez et al. 1994; Lopez-Barneo et al. 2001). Because hypoxia inhibits certain classes of K+ channels (see below), measurements of K+ conductances are also regarded as measures of O2 sensing, especially in isolated type I cells and in carotid body slice preparations (Lopez-Barneo et al. 2001). There is no doubt that transmitter release and ion channel responses represent excellent examples of cellular responses to hypoxia. However, extrapolating cellular responses to overall output of the carotid body has to be viewed with caution because these recordings need not necessarily reflect afferent nerve activation (Donnelly, 1996, 1999). Given this limitation, for understanding the functional O2 sensing at the organ level, it is important to corroborate the cellular measures of O2 sensing with measures of sensory activity.
Transduction process: proposed O2 sensors
Haem-containing proteins as O2 sensors (metabolic hypothesis). The stimulus–response curve of the carotid body is hyperbolic and resembles the inverted (i.e. mirror image) haemoglobin (Hb)–O2 dissociation curve. Given the similarity between the Hb–O2 dissociation curve and the carotid body sensory response to hypoxia, it was thought that Hb-like molecule (or haem-containing protein) functions as O2 sensor. There have been intense efforts to identify the haem-containing protein(s) that serves as O2 sensor(s).
Mitochondrial cytochrome oxidases contain haem, and inhibitors of mitochondrial respiratory chain augment the sensory discharge similar to hypoxia. Consequently, it was proposed that mitochondrial cytochrome(s) functions as O2 sensor (metabolic hypothesis), especially the cytochrome a3, which has a low affinity for O2 (Mills & Jobsis, 1970). Subsequent studies extensively examined the potential role of mitochondrial cytochromes in O2 sensing by the carotid body. Antimycin A, which blocks the complex III of the mitochondria, prevents the hypoxic but not the CO2 response of the carotid body (Mulligan & Lahiri, 1982). High concentrations of carbon monoxide (CO) stimulated the carotid body and this effect was reversed in the presence of light, most probably preventing the binding of CO to cytochrome C (Warburg effect; see Lahiri & Acker, 1999). The stimulatory effect of CO coincided with inhibition of cytochrome(s), possibly of mitochondrial origin, as evidenced by spectral analysis (Lahiri & Acker, 1999). This led to the idea that the transduction involves inhibition of cytochrome oxidase(s).
Several non-mitochondrial enzymes contain haem, and molecular O2 is required for their enzymatic activity. Examples of this class of molecules include nitric oxide synthase (NOS), haem oxygenase 1 and 2 (HO-1 and 2, respectively), and NADPH oxidases. HO-2 is expressed in type I cells, and neuronal NOS in nerve fibres that innervate the carotid body in close proximity to type I cells. Being a highly diffusible molecule, NO can affect type I cell function (Prabhakar et al. 1995; Prabhakar, 1999). HO-2 and NOS catalyse the formation of CO and NO, respectively. Pharmacological blockers of HO-2 and NOS augment, while exogenous administration of low concentrations of NO and CO inhibit, the sensory activity of the carotid body. Based on these studies, it has been proposed that hypoxia augments the carotid body activity by inhibiting NOS and HO-2 leading to decreased formation of NO and CO, respectively (Prabhakar, 1999). In other words, like mitochondrial cytochromes, NOS and HO-2 may serve as O2 sensors. Diphenyliodinium, a purported inhibitor of NADPH oxidase, prevents the sensory response to hypoxia, and NADPH oxidase is expressed in the type I cells. Given that molecular O2 is necessary for catalytic activity of NADPH oxidase, it was proposed that it might also serve as O2 sensor (Acker et al. 1989). The studies described thus far suggest that several haem-containing proteins, either of mitochondrial or non-mitochondrial origin, might function as potential O2 sensors in the carotid body.
Ion channels as O2 sensors (membrane hypothesis). Based on the neuronal phenotype of type I cells, it was thought (Gonzales et al. 1994) that hypoxia directly depolarizes type I cells causing an influx of Ca2+ through voltage-gated Ca2+ channels leading to release of transmitters, and afferent nerve activation (membrane hypothesis). Electrophysiological studies have shown that hypoxia depolarizes many type I cells (Pang & Eyzaguirre, 1992). Studies using the patch-clamp technique suggested that hypoxia-induced depolarization of type I cells is due to inhibition of a certain class of K+ currents in type I cells (Lopez-Barneo et al. 2001). The type of K+ current inhibited by hypoxia, however, varies with species. In rabbit type I cells, hypoxia inhibits the transient K+ current, whereas in rat type I cells, low PO2 inhibits a large conductance Ca2+-activated K+ current. A recent study suggests that Kv3 functions as an O2-sensing K+ channel in the mouse carotid body (Perez-Garcia et al. 2004). Although pharmacological blockade of Ca2+-dependent K+ currents mimics the effects of hypoxia in carotid body slices, as evidenced by enhanced transmitter release under normoxia (Lopez-Barneo et al. 2001), the blockers did not consistently augment the sensory activity of the intact carotid body during normoxia (see Donnelly, 1999 for ref.). Neither the transient K+ current nor the large conductance Ca2+-sensitive K+ channel are active at the resting membrane potential of the ‘single’ type I cells in isolation.
Other studies, however, identified other K+ conductances in type I cells that are active at the resting membrane potential of the type I cells. These include background and/or leak K+ conductance in rat type I cells (Buckler, 1999), and human ether-à-go-go (HERG)-like inward rectifying K+ current in rabbit (Overholt et al. 2000). The biophysical characteristics of the background or leak K+ conductance resemble twin-pore acid-sensitive K+ (TASK-like) channels and lack intrinsic voltage sensitivity or time dependence. Hypoxia inhibits the leak K+ conductance in rat type I cells (Buckler, 1999), as do metabolic inhibitors (e.g. cyanide and uncouplers of oxidative phosphorylation; Wyatt & Buckler, 2004), which are known to augment the sensory activity.
HERG-like channel is active at the resting membrane potential and blockade of this channel results in depolarization of type I cells, elevation of cytosolic [Ca2+] and augmentation of sensory activity during normoxia (Overholt et al. 2000). It is interesting that HERG channel protein contains a Per Arnt Sim (PAS) domain that is highly conserved among the redox-sensitive proteins. Hypoxia-sensitivity of the HERG channel has not yet been demonstrated.
The studies described above demonstrate that type I cells express a variety of O2-sensitive K+ channels in type I cells and hypoxia inhibits these channels. In this scenario, O2-sensitive K+ channels might also serve as O2 sensors in the carotid body.
Interaction between putative O2 sensors (chemosome hypothesis).
It is evident from the above studies that the carotid body is endowed with multiple putative O2 sensors. Considerable evidence exists supporting a role for of each one of these molecules in the transduction process. What might be the need for multiple O2 sensors? As pointed out above, O2 sensing by the carotid body is unique in that it senses a wide range of PO2 levels (80–20 mmHg) with extreme rapidity (i.e. seconds). Given the range of the O2 affinities of various haem-containing proteins expressed in the type I tissue, it is possible that each of them might serve as a sensor for a given PO2 level allowing the carotid body to respond to a broad range of levels of PO2. Because the response of ion channels to hypoxia occurs in less than a second, it is conceivable that the rate of inhibition of K+ channels might contribute to the rapidity of the carotid body response to hypoxia. In this scenario, the functional expression of O2 sensing in the carotid body (both in terms of range PO2 levels and speed of the response) requires the contribution from both the haem-containing proteins and O2-sensitive K+ channels, the former for conferring sensitivity to wide range of PO2 levels and the later for the rapidity of the response. Based on these considerations, it has been proposed that the transduction involves an ensemble of, and interactions between, haem-containing proteins and O2-sensitive ion channel proteins functioning as a chemosome (Prabhakar & Peng, 2004; Prabhakar & Jacono, 2005). The salient features of the ‘chemosome’ hypothesis are schematically presented in Fig. 1. A recent study by Williams et al. (2004) demonstrated an interaction between haem-containing and O2-sensitive K+ channel proteins. These investigators reported that HO-2 interacts with 
and ß subunits of the Ca2+-activated K+ channel, and O2 sensing by the channel is lost by disrupting the HO-2 by the silencing RNA technique. While these observations lend support to the chemosome hypothesis, further studies are required to determine whether disruption of HO-2 alters the sensory response of the intact carotid bodies to hypoxia.
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Several lines of evidence suggest that neurotransmitters are critical for hypoxia-induced afferent nerve activation. Neurotransmitters expressed in the carotid body can be classified into two major categories: conventional and unconventional. The conventional class of neurotransmitters includes those stored in synaptic vesicles and mediates their actions via activation of specific membrane-bound receptors often coupled to G-proteins. Members of this class of transmitters include: (a) biogenic amines (acetylcholine (Ach), dopamine, noradrenaline (norepinephrine) and 5-hydroxytryptamine); (b) neuropeptides (enkephalins, substance P and endothelins); (c) ATP; and (d) amino acids (e.g. GABA; see Kumar et al. 2003 for ref.). Recent studies have shown that histamine (Koerner et al. 2004) and angiotensin II (Leung et al. 2003) are also expressed in the carotid body. Unconventional neurotransmitters/modulators are those that are not stored in synaptic vesicles, but are spontaneously generated via enzymatic reactions and exert their biological actions either by interacting with cytosolic enzymes or by direct modification of proteins. Gas molecules such as NO and CO belong to the category of unconventional neurotransmitters and the enzymes associated with the synthesis of NO and CO are expressed in the carotid body (Prabhakar, 1999). It is interesting that the enzymes associated with generation of NO and CO might function as O2 sensors by virtue of them containing haem, whereas their reaction products serve the role of transmitters/modulators in the carotid body.
Like elsewhere in the nervous system, some of the transmitters (e.g. ACh, substance PSP and ATP) stimulate, whereas others (e.g. dopamine and enkephalins) inhibit afferent nerve activity of the carotid body. Which of the transmitter(s) is responsible for hypoxia-induced afferent nerve activation? Because hypoxia activates the afferent nerve ending it was assumed that low PO2 releases exclusively excitatory transmitter(s). However, studies have shown that hypoxia releases both inhibitory (e.g. dopamine) and excitatory (e.g. SP and ACh) transmitters from the carotid body (Fitzgerald et al. 1999; Kim et al. 2001, 2004). Hence the idea that low PO2 releases only the excitatory transmitter is no longer tenable. The potential roles of excitatory transmitters such as SP and ACh in hypoxia-induced afferent activation and the importance of NO and CO in the carotid body have been reviewed elsewhere (Kumar et al. 2003), and will not be elaborated upon here.
Identity of the excitatory transmitter for afferent nerve activation by hypoxia: is it ATP?
ATP is stored along with other transmitters in secretory vesicles and functions as a cotransmitter. Its biological actions are mediated via activation of purinergic receptors of the P2X and P2Y family. From the early studies of Joels & Neil (1968), it is known that ATP leads to prompt excitation followed by inhibition of the carotid body sensory activity. In recent years, there has been considerable evidence supporting a role for ATP as an excitatory transmitter that mediates afferent nerve activation by hypoxia (see recent reviews by Iturriaga & Alcayaga, 2004; Nurse, 2005 for references). Studies by Prasad et al. (2000) indicate the expression of P2X2–P2X3 receptors on afferent nerves near type I cells and soma of the petrosal neurones. Once released, ATP can act on type I cells in an autocrine fashion as well as on the afferent nerve ending. Consistent with its action on type I cells is the observation that ATP increases cytosolic [Ca2+] in type I cells (Mokashi et al. 2003). On the other hand, Xu et al. (2005) found no effect of ATP on resting cytosolic [Ca2+] in type I cells isolated from rat carotid bodies. However, they found that ATP strongly inhibits hypoxia-evoked increase in cytosolic [Ca2+] in type I cell, and this effect seems to be mediated by P2Y receptors. Suramin, a non-selective purinergic blocker, markedly attenuates the sensory response to hypoxia in ex vivo carotid bodies (Zhang et al. 2000) suggesting that purinergic receptors are involved in afferent nerve activation. The most convincing evidence for a critical role of ATP in afferent nerve activation comes from the studies on genetically engineered mice lacking P2X2 receptors. In these mice, the hypoxic sensory response of the carotid body is markedly blunted resulting in an attenuated hypoxic ventilatory response, whereas such an attenuation of the hypoxic sensory response was not seen in mice lacking P2X3 receptors (Rong et al. 2003). The role for ATP is further supported by a recent finding that hypoxia releases ATP from the carotid body (Buttigieg & Nurse, 2004).
Is ATP alone sufficient for the full expression of the sensory response to hypoxia? Based on pharmacological approaches, Zhang et al. (2000) suggested that co-release of ACh and ATP is necessary for the full expression of sensory excitation by low PO2. However, whether or not hypoxia releases ACh from the carotid body is controversial. Fitzgerald et al. (1999) reported that hypoxia (4% O2) combined with 2% CO2, led to the release of ACh from the cat carotid body. On the other hand, Kim et al. (2004) found no effect of hypoxia on ACh release, whereas CO2 was more potent in evoking its release from the rabbit carotid bodies. However, these authors found that hypoxia did evoke ACh release in the presence of muscarinic receptor blockers, suggesting that muscuranic receptors exert inhibitory influence on ACh release by hypoxia (Kim et al. 2004). Given that sensitivity to hypoxia of the carotid body depends on the prevailing PCO2 (the higher the PCO2, the greater the hypoxic sensitivity (Lahiri & DeLaney, 1975), and the fact that hypercapnia facilitates ACh release (at least from rabbit carotid bodies), it is possible that co-release of ACh and ATP might be of importance in conferring O2–CO2 interaction at the carotid body. Such a possibility seems partly justified in view of a recent report by Zhang & Nurse (2004) showing that blockade of ATP receptors also prevents sensory excitation by CO2. Because ATP is co-stored with a variety of other transmitters, it is also possible that ATP can facilitate the actions of excitatory transmitters in addition to ACh and such interaction might be crucial for the full expression of the afferent nerve activation by hypoxia. Nonetheless, ATP, either by itself or acting in concert with other transmitters, seems to be important for afferent nerve activation by hypoxia. In this context it is interesting to note that ATP, an end product of oxidative metabolism, which requires molecular oxygen turned out be an important molecule for mediating the sensory response to hypoxia.
Push–pull mechanism of inhibitory transmitters
As stated above, hypoxia releases both excitatory and inhibitory neurotransmitters from the carotid body. What could be the significance of inhibitory transmitters in afferent nerve excitation by hypoxia? It has been established that the carotid body is a slowly adapting type of sensory receptor in that the increase in sensory discharge evoked by hypoxia is maintained more or less during the entire duration of the stimulus. If an excitatory transmitter alone participates in the sensory transmission, then one would expect only a brief excitation followed by a prompt return to baseline discharge, despite maintaining the hypoxic stimulus. In other words, sensory excitation will no longer be maintained during the entire period of hypoxia. On the other hand, if the inhibitory messengers are co-released then they will aid in producing sustained excitation by preventing the overexcitation caused by excitatory transmitter as illustrated schematically in Fig. 2. Thus, excitatory and inhibitory messengers act in concert like a push–pull mechanism (Prabhakar, 1994). Indeed, many biological processes are regulated by such a push–pull mechanism involving interactions between excitatory and inhibitory messenger molecules. Therefore, it is conceivable that excitatory transmitters such as ATP, either alone or in co-operation with other excitatory transmitters, initiate the afferent nerve activation by hypoxia, whereas sustained excitation is achieved via a complex interplay between excitatory and inhibitory neurochemicals. Perhaps, the push–pull-like interactions between excitatory and inhibitory chemicals might play a more important role in carotid body plasticity associated with chronic hypoxic conditions than under ‘normal’ conditions.
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In this brief review, I have attempted to summarize the potential roles of putative O2 sensors in the transduction process and the role of excitatory and inhibitory transmitters in afferent nerve excitation by hypoxia in the carotid body. From the available evidence, it appears that the transduction (O2 sensing) process involves functional interactions between haem-containing proteins and ion channels working in concert like a chemosome that would allow the carotid body to respond to a broad range of PO2 levels with extreme rapidity. Future studies involving genetically engineered mice with targeted disruption of one or more of the putative O2 sensors might provide more mechanistic insights into the O2 sensing at the carotid body. Furthermore, given the fundamental importance of CO2 in determining the magnitude of the sensory response to a given level of hypoxia, it is important to test whether the O2 sensing ability of a given putative O2 sensor depends on the prevailing PCO2. Although there may be a role for ATP as an excitatory molecule for afferent nerve activation by hypoxia, it would be of interest to determine whether the sensory response to CO2 is also affected in the carotid bodies in mice deficient in P2X2 receptors. Much still needs to be elucidated with regard to the role of interactions between various transmitters in the afferent nerve activation by hypoxia.
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 C. N. Wyatt, K. J. Mustard, S. A. Pearson, M. L Dallas, L. Atkinson, P. Kumar, C. Peers, D. G. Hardie, and A. M. Evans AMP-activated Protein Kinase Mediates Carotid Body Excitation by Hypoxia J. Biol. Chem., March 16, 2007; 282(11): 8092 - 8098. [Abstract] [Full Text] [PDF]
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T. A. Day and R. J. A. Wilson Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation J. Physiol., February 1, 2007; 578(3): 843 - 857. [Abstract] [Full Text] [PDF]
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