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¹ Department of Physiology, Royal Free and University College London Medical School, Rowland Hill Street, London NW3 2PF² Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK

	Abstract

Top Abstract Introduction Conclusion: A unifying... References

 
Recent evidence suggests that ATP is a mediator of central (within the ventral surface of the medulla) and peripheral (within the carotid body) chemosensory transduction. This short review discusses the data obtained in experiments in vivo and in vitro supporting this hypothesis. P2 receptors for ATP are expressed within the ventrolateral medulla as well as by the peripheral chemosensory afferent neurones. Blockade of P2 receptors in the ventrolateral medulla attenuates the CO₂-induced increase in respiration while blockade of purinergic signalling impairs carotid body function and diminishes the ventilatory response to hypoxia. Furthermore, ATP is released from the ventral surface of the medulla during hypercapnia and from the carotid body during hypoxia. Finally, exogenous ATP applied on the ventral surface of the medulla evokes rapid increase in phrenic nerve activity, while ATP applied to the carotid body evokes marked excitation of the carotid sinus nerve afferents. We suggest that in the ventrolateral medulla ATP is produced following CO₂/H⁺-induced activation of central chemosensory elements (neuronal and/or glial) and acts within the respiratory network to produce physiologically relevant changes in ventilation. In the carotid body, ATP contributes in a significant manner to the transmission of the sensitivity of the carotid body to changes in arterialP_O2and may be considered as a key transmitter released by chemoreceptor cells to activate endings of the sinus nerve afferent fibres.

(Received 1 October 2003; accepted after revision 3 November 2003)
Corresponding author A. V. Gourine: Department of Physiology, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK. Email: a.gourine{at}rfc.ucl.ac.uk

	Introduction

Top Abstract Introduction Conclusion: A unifying... References

 
Under normal physiological conditions blood and brain P_O2 and P_CO2 are maintained at constant levels by neural activity that controls breathing. Central respiratory drive is sensitive to changes in arterial P_O2 and P_CO2 which are monitored by the peripheral chemoreceptors located within the carotid bodies, and in some species in the aortic bodies, and by chemoreceptors within the central nervous system (Gonzalez et al. 1994; Daly, 1997; Nattie, 1999; Prabhakar, 2000). In adult mammals the glomus cells of the carotid body are the major peripheral P_O2 chemosensitive elements (Gonzalez et al. 1994; Prabhakar, 2000; Lahiri et al. 2001). These cells detect changes in arterial P_O2 and transmit this information to the chemoafferent nerve fibres of the carotid sinus nerve, which relays to the brainstem respiratory centres to produce adaptive changes in ventilation. Levels of CO₂ are monitored predominantly by the central chemoreceptors localized within the medulla oblongata (Daly, 1997; Nattie, 1999). The ventilatory response to hypercapnia is largely preserved in experimental animals after denervation of the carotid and aortic bodies and according to the estimate of Heeringa et al. (1979) up to 80% of the CO₂-evoked response is mediated by the action of CO₂ at the brainstem chemosensitive sites.

There has been increasing interest in the role of purines in the nervous system. Extracellular ATP acting through ionotropic P2X and metabotropic P2Y receptors, acts as a signalling molecule in the brain and periphery and has numerous physiological functions (Ralevic & Burnstock, 1998; North, 2002). Interestingly, immunohistochemical studies demonstrate the presence of ionotropic P2X receptors of the ATP-gated ion channel in central chemosensitive areas within the brainstem as well as in the carotid bodies (Kanjhan et al. 1999; Yao et al. 2000; Prasad et al. 2001; Thomas et al. 2001). The role of purinergic signalling in central and peripheral mechanisms of chemosensitivity has been studied extensively in our laboratory over the last 5 years. Results obtained to date suggest that ATP is a common mediator of chemosensory transduction in the central chemosensitive area within the ventrolateral medulla (VLM) as well as in the carotid body.

Purinergic signalling in central CO₂ chemosensitivity

The ventral surface of the medulla functions as a primary central chemoreceptive area (Loeschcke, 1982; Ballantyne & Scheid, 2000), although other structures of the hindbrain have been reported to be chemoreceptive (Nattie, 1999). Whilst the mechanisms of this chemosensitivity remain largely unknown, it is apparent that changes in [H⁺], that follow changes in P_CO2 represent the adequate stimulus for central chemosensitive neurones (Cherniack, 1993; Ritucci et al. 1998). The VLM also contains a network of respiratory neurones responsible for generation of the respiratory rhythm as well as premotor neurones responsible for transmitting this rhythm to spinal motoneurones controlling the diaphragm and intercostal muscles (Richter et al. 1992; McCrimmon et al. 2000; Richter & Spyer, 2001). There is evidence suggesting that at least some VLM neurones with respiratory-related activity are intrinsically sensitive to the changes in [H⁺] that follow changes in arterial P_CO2 (Kawai et al. 1996).

P2X Receptors are Sensitive to Changes in Extracellular [H⁺]

An interesting feature of the P2X receptors is that their sensitivity to ATP depends upon extracellular pH. In human embryonic kidney cell line (HEK293) cells transfected with P2X₁, P2X₃ and P2X₄ subunits, the currents evoked by ATP are reduced by acidification of the extracellular environment (Stoop et al. 1997). Conversely, in HEK293 cells and in Xenopus oocytes transfected with P2X₂ subunit, the currents induced by ATP application are potentiated by lowering the external pH (King et al. 1996; Stoop et al. 1997; Wildman et al. 1997). P2X₂ homomeric receptors are unique in terms of high sensitivity to the external pH within the physiological range 7.1–7.4 (King et al. 1997; Wildman et al. 1997). As ATP-evoked currents at functional heteromeric P2X_2/6, P2X_1/2 and P2X_2/3 receptors in expression systems are also increased by acidification (Stoop et al. 1997; King et al. 2000; Brown et al. 2002), it appears that the P2X₂ subunit confers the sensitivity to [H⁺] changes on to the heteromultimeric channels. Based on this evidence we suggested initially that if VLM respiratory neurones possess P2X receptors, their chemosensitivity may be due in part to shifts in local pH that would change the sensitivity of P2X receptors to a basal ATP-tone.

P2X receptors and hypercapnia-evoked changes in respiration

Our data indeed support a role for P2 receptors in respiratory control (Spyer & Thomas, 2000). In anaesthetized and artificially ventilated rats the P2 receptor antagonist suramin attenuates the respiratory responses to changes in arterial P_CO2 when microinjected into the VLM (Thomas et al. 1999). Furthermore, microionophoretic application of P2 receptor antagonists suramin or pyridoxal-5'-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) completely blocks hypercapnia-evoked increases in the activity of preinspiratory and inspiratory VLM neurones (Thomas & Spyer, 2000). Interestingly, although postinspiratory and expiratory neurones were excited by increasing levels of inspired CO₂, and also by ionophoretically applied ATP, the CO₂-evoked effects were unaffected by P2 receptor blockade (Thomas & Spyer, 2000). These data suggested that certain P2 receptors localized within the VLM contribute to the respiratory response evoked by an increase in the level of the inspired CO₂. Furthermore ATP acting on these receptors may be responsible for the increases in activity of preinspiratory and inspiratory neurones during hypercapnia.

Tonic influence of ATP on VLM respiratory network

Any hypothesis that proposes a key role for the pH sensitivity of P2X receptors in mediating chemosensitivity, would have to involve tonic release of ATP and consequent activation of P2X receptors. This is potentially testable through the use of P2 receptor antagonists.

Suramin injected bilaterally into the VLM of anaesthetized and artificially ventilated rats not only attenuated respiratory response to hypercapnia, but also significantly reduced basal (i.e. during normocapnia) phrenic nerve activity, in some cases causing complete cessation of the central respiratory drive (Thomas et al. 1999). Similarly, ionophoretic application of P2 receptor antagonists suramin or PPADS reduces baseline firing in a significant proportion of preinspiratory, inspiratory and expiratory VLM neurones (Thomas & Spyer, 2000; Gourine et al. 2003).

Given the caveat that both suramin and PPADS can target other receptors (notably glutamate receptors) our results suggest that during normocapnia, the VLM respiratory network could be under a tonic excitatory influence of ATP mediated through as yet unknown P2 receptors.

P2X₂ receptor subunit expression in VLM respiratory neurones

Expression of P2X₁, P2X₂, P2X₅ and P2X₆ receptor subunits has been demonstrated in the VLM (Kanjhan et al. 1999; Yao et al. 2000; Thomas et al. 2001). However, the high sensitivity of the P2X₂ receptor subtype to changes in pH suggested that if P2X receptors are responsible for central CO₂/pH sensitivity they would likely contain P2X₂ receptor subunit. By extension therefore, it would be very interesting if VLM respiratory neurones express this receptor subunit.

A significant proportion of the VLM respiratory neurones do indeed express the P2X₂ receptor subunit. P2X₂ receptor subunit immunoreactivity was detected in 50% of expiratory neurones and in 20% of neurones with inspiratory-related discharge: preinspiratory and inspiratory (Gourine et al. 2003). Furthermore microionophoretic application of ATP increased the activity of 80% of expiratory neurones and of 30% of VLM neurones with inspiratory-related discharge (Gourine et al. 2003).

Plausible neuronal mechanisms

The data described above suggested that P2X₂ receptors may contribute to CO₂-induced excitation of at least the neurones that express these receptors. However, the unexpected finding was that in the VLM only approximately 20% of inspiratory neurones contain P2X₂ immunoreactivity, indicating that the proportion of VLM neurones with inspiratory-related discharge that express P2X₂ receptor subunit is smaller than the proportion of these cells that are excited during hypercapnia. An earlier study showed that increasing inspired CO₂ excited 85% of inspiratory and 66% of preinspiratory neurones in the area of rostral VLM (Thomas & Spyer, 2000). In all cases this CO₂-induced excitation was reduced or abolished by suramin or PPADS (Thomas & Spyer, 2000).

One possible explanation for this apparent discrepancy is that P2X receptors that contain P2X₂ receptor subunits are located presynaptically or on ‘non-respiratory’ VLM neurones that are activated during hypercapnia and provide excitatory drive to the neurones with inspiratory-related discharge. Therefore, VLM neurones may not necessarily express P2X₂ receptor proteins to exhibit chemosensitivity. Sensitivity to P_CO2/[H⁺] could be a property of other VLM neurones which may not have respiratory-related modulation of their activity. If this were the case, then the effect of P2 receptor antagonists on changes in activity of VLM preinspiratory and inspiratory neurones during hypercapnia could be explained by their action on the adjacent chemosensitive elements that express P2X₂ receptor subunits and provide excitatory drive to the VLM neurones with inspiratory-related discharge. However, this mechanism would require either electrical coupling between these putative chemosensitive neurones and VLM inspiratory neurones (not yet documented – and which would reveal at the very least changes in membrane potential that would be linked to the respiratory pattern) or intact chemical synaptic transmission. As shown by Kawai et al. (1996) the latter is not essential, since VLM inspiratory neurones demonstrate inherent chemosensitivity to changes in P_CO2/[H⁺] in the presence of tetrodotoxin or under conditions of greatly reduced synaptic transmission.

Conversely, it is possible that the sensitivity of VLM inspiratory neurones to changes in P_CO2/[H⁺] is also mediated by P2 receptors that do not contain P2X₂ receptor subunits, perhaps by metabotropic P2Y receptors or by P2X₃, P2X₄, P2X₅ receptors all of which have been identified immunohistochemically in the VLM in addition to P2X₂ (Yao et al. 2000; Thomas et al. 2001). This possibility seemed even more likely when experiments in P2X₂ knockout mice revealed that neither the resting ventilation nor the ventilatory response to increasing levels of CO₂ in the inspired air were affected by the absence of P2X₂ receptor subunits (Gourine, Rong, Burnstock & Spyer, unpublished observations). Two possibilities thus remain. Firstly, P2X receptors that contain the P2X₂ receptor subunit are not essential for CO₂ chemoreception and ventilatory responses to hypercapnia in mice. Or secondly, that P2X receptors that contain the P2X₂ receptor subunit do indeed play a role in the mechanism underlying ventilatory response to hypercapnia, but that this role cannot be identified functionally in P2X₂ deficient mice as these animals are able to compensate for the absence of this specific gene with the increased expression of one, or several other genes. We feel that this latter explanation is probably less likely as the P2X₂ deficient mice exhibit attenuated responses to hypoxia (see below) and are thus unable to compensate for the loss of this receptor subunit in at least one other functional context.

Thus, given the data available at the moment, we conclude that P2X receptors other than, or in addition to, P2X₂, or P2Y receptors may be involved in mediating hypercapnia-induced changes in the activity of VLM neurones with inspiratory-related discharge.

Rapid release of ATP on the ventral surface of the medulla oblongata during hypercapnia

The possible involvement of ATP and P2 receptors in mediating chemosensitivity has recently taken a new turn with our direct real-time measurement of ATP release during hypercapnia.

In anaesthetized and artificially ventilated rats we have shown, using amperometric enzymatic ATP biosensors, that hypercapnia induced a rapid and marked increase in the concentration of ATP on the ventral surface of the medulla (Gourine, Llaudet, Dale & Spyer, unpublished observations). This increase coincided with the enhancement of the amplitude of the phrenic nerve bursts induced by hypercapnia. Further in vitro experiments demonstrated that acidification (decrease in pH from 7.4 to 7.0) evoked ATP release from horizontal slices that contained the ventral surface of the medulla (Gourine, Llaudet, Dale & Spyer, unpublished observations).

These data indicate that ATP is released from the ventral surface of the medulla during hypercapnia due to activation of central chemoreceptors. We suggest that during hypercapnia a rapid increase in extracellular concentration of ATP and its action on P2 receptors localized within the VLM is responsible for the increases in activity of medullary inspiratory neurones and therefore for the overall augmentation of the central respiratory output. We now modify our original hypothesis to propose that it is the CO₂-induced release of ATP into the extracellular fluid in the VLM, rather than pH-induced increases in the sensitivity of certain P2 receptors to ATP, that underlies the involvement of purinergic signalling in the mechanisms of central chemosensitivity (Fig. 1A).

View larger version (24K): [in this window] [in a new window]   Figure 1.  Hypothetical models of ATP involvement in central and peripheral chemosensory transduction A, hypothesis for chemoreception in the surface of the ventral medulla. Glial cells on the outer layer are intrinsically chemosensitive (cf. Okada et al. 2002) and during hypercapnia they release ATP to act via P2 receptors on the dendritic endings of more dorsally located secondary chemosensitive neurones and/or respiratory neurones. The activity of these neurones feeds into the respiratory central pattern generator (CPG) and enhances ventilatory activity. Within the primary chemoreceptors, hypercapnia or acidification is proposed to cause depolarization (Vm) through an action on K+ channels possibly of the TASK or KIR types. The depolarization leads to the release of ATP in a tetrodotoxin-insensitive manner. B, in the carotid body, P2X receptors containing the P2X2 subunit play a pivotal role in transmitting information about arterial PO2 and PCO2 levels. Decrease in PO2 or an increase in PCO2/H+ activate glomus cells which release ATP as the main transmitter to stimulate afferent terminals of the sinus nerve via interaction with P2X receptors that contain the P2X2 subunit, with or without P2X3 subunit. Other putative chemosensory transduction mechanisms (including, e.g. Ach and other transmitters) are not shown for presentation purposes.

There is considerable evidence suggesting that ATP may be a key mediator of chemosensory transduction in the carotid body. P2X₂ and P2X₃ receptor subunits have been shown to be localized on the rat carotid body afferents (Prasad et al. 2001). Experiments in a coculture preparation consisting of dispersed rat carotid body glomus cells and dissociated petrosal neurones showed that ATP is involved in chemotransmission in the carotid body (Zhang et al. 2000; Prasad et al. 2001). Zhang et al. (2000) showed that a hypoxic stimulus is sensed by the glomus cells, and that the chemotransmission to nearby petrosal neurones can be blocked by a coapplication of the P2 receptor antagonist suramin with a nicotinic ACh receptor blocker. This indicates that the corelease of ATP and Ach may be involved in chemotransmission in the carotid body.

To obtain conclusive evidence for or against the role of ATP-mediated purinergic signalling in the carotid body we have investigated the ventilatory responses to hypoxia and carotid body function in mice with selective deletion of genes encoding P2X₂, P2X₃, or both subunits (Cockayne et al. 2000, 2002). We have demonstrated that in mice, P2X₂ deficiency results in an attenuation of the ventilatory response to hypoxia and in a dramatic reduction in the responses of the carotid sinus nerve to a decrease in P_O2 in the in vitro carotid body/sinus nerve preparation (Rong et al. 2003). We have also shown that ATP and its stable analogue, ,ß-meATP, evoke rapid excitation of the sinus nerve afferents and that PPADS virtually abolishes hypoxia-induced increase in sinus nerve discharge (Rong et al. 2003). Consistent with previous studies in rats (Prasad et al. 2001), we have found that in mice both P2X₂ and P2X₃ receptor subunit immunoreactivities are present on afferent terminals of the sinus nerve surrounding clusters of glomus cells. Finally, in the isolated carotid body/sinus nerve preparation of the rat and mouse we have shown using amperometric enzymatic biosensors that a decrease in P_O2 induces rapid release of ATP from the carotid body (Gourine, Llaudet, Dale & Spyer, unpublished observations).

These results indicate that in the carotid body, P2X receptors containing the P2X₂ subunit play a pivotal role in transmitting information about arterial P_O2 levels, and are therefore essential for a normal respiratory response to hypoxia. Since in the carotid body P2X₂ and P2X₃ immunoreactivities were detected on nerve terminals rather than on the glomus cells, we suggest that during hypoxia, O₂-sensing glomus cells release ATP as the main transmitter to stimulate afferent terminals of the sinus nerve via interaction with P2X receptors that contain the P2X₂ subunit, with or without P2X₃ subunit (Fig. 1B).

	Conclusion: A unifying hypothesis

Top Abstract Introduction Conclusion: A unifying... References

 
The data discussed above allow us to propose a unifying hypothesis of central and peripheral chemosensory transduction, which involves ATP as a common key mediator (summarized in Fig. 1). Indeed, ATP is released from the ventral surface of the medulla during hypercapnia and from the carotid body during hypoxia. Blockade of the P2 receptors within the VLM attenuates the respiratory response evoked by hypercapnia, while blockade of the P2X receptors in the carotid body (or their elimination in the knockout mice) greatly diminishes the ventilatory response to hypoxia and impairs carotid body function. ATP applied to the ventral surface of the medulla evokes a rapid increase in phrenic nerve activity, while ATP applied to the carotid body evokes rapid excitation of the carotid sinus nerve afferents. Finally, P2X receptors are expressed by the VLM respiratory neurones as well as by the peripheral chemosensory afferent neurones which relay information to the brainstem.

Our results give convincing evidence in favour of ATP-mediated purinergic signalling having a pivotal role in chemosensory control of the respiratory function. We suggest that any failure of expression of P2 receptors, or a functional blockade of these receptors, may have major consequences for respiratory control. This may be a critical factor at, or soon after, birth and at other times of respiratory stress.

	Footnotes

 
Presented at a meeting of the Physiological Society at Trinity College Dublin in July 2003.

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	Acknowledgements

 
The experimental work described in this paper was supported by the Biotechnology and Biological Sciences Research Council (UK) and the Wellcome Trust (UK).

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