Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 329 (5991): 571-575

Copyright © 2010 by the American Association for the Advancement of Science

Astrocytes Control Breathing Through pH-Dependent Release of ATP

Alexander V. Gourine,1,* Vitaliy Kasymov,1 Nephtali Marina,1 Feige Tang,2 Melina F. Figueiredo,2 Samantha Lane,2 Anja G. Teschemacher,2 K. Michael Spyer,1 Karl Deisseroth,3 Sergey Kasparov2,*

Abstract: Astrocytes provide structural and metabolic support for neuronal networks, but direct evidence demonstrating their active role in complex behaviors is limited. Central respiratory chemosensitivity is an essential mechanism that, via regulation of breathing, maintains constant levels of blood and brain pH and partial pressure of CO2. We found that astrocytes of the brainstem chemoreceptor areas are highly chemosensitive. They responded to physiological decreases in pH with vigorous elevations in intracellular Ca2+ and release of adenosine triphosphate (ATP). ATP propagated astrocytic Ca2+ excitation, activated chemoreceptor neurons, and induced adaptive increases in breathing. Mimicking pH-evoked Ca2+ responses by means of optogenetic stimulation of astrocytes expressing channelrhodopsin-2 activated chemoreceptor neurons via an ATP-dependent mechanism and triggered robust respiratory responses in vivo. This demonstrates a potentially crucial role for brain glial cells in mediating a fundamental physiological reflex.

1 Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, UK.
2 Department of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK.
3 Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.

* To whom correspondence should be addressed. E-mail: a.gourine{at} (A.V.G.); sergey.kasparov{at} (S.K.)

Purinergic signalling contributes to chemoreception in the retrotrapezoid nucleus but not the nucleus of the solitary tract or medullary raphe.
C. R. Sobrinho, I. C. Wenker, E. M. Poss, A. C. Takakura, T. S. Moreira, and D. K. Mulkey (2014)
J. Physiol. 592, 1309-1323
   Abstract »    Full Text »    PDF »
Autocrine regulation of glioma cell proliferation via pHe-sensitive K+ channels.
A. Honasoge, K. A. Shelton, and H. Sontheimer (2014)
Am J Physiol Cell Physiol 306, C493-C505
   Abstract »    Full Text »    PDF »
Cell type-specific and time-dependent light exposure contribute to silencing in neurons expressing Channelrhodopsin-2.
A. M. Herman, L. Huang, D. K. Murphey, I. Garcia, and B. R. Arenkiel (2014)
eLife Sci 3, e01481
   Abstract »    Full Text »    PDF »
Oligodendrocyte Lineage Cells Contribute Unique Features to Rett Syndrome Neuropathology.
M. V. C. Nguyen, C. A. Felice, F. Du, M. V. Covey, J. K. Robinson, G. Mandel, and N. Ballas (2013)
J. Neurosci. 33, 18764-18774
   Abstract »    Full Text »    PDF »
Astrocytes in the Rat Nucleus Tractus Solitarii Are Critical for Cardiovascular Reflex Control.
L.-H. Lin, S. A. Moore, S. Y. Jones, J. McGlashon, and W. T. Talman (2013)
J. Neurosci. 33, 18608-18617
   Abstract »    Full Text »    PDF »
Glial cells modulate the synaptic transmission of NTS neurons sending projections to ventral medulla of Wistar rats.
D. Accorsi-Mendonca, D. B. Zoccal, L. G. H. Bonagamba, and B. H. Machado (2013)
PHY2 1, e00080
   Abstract »    Full Text »    PDF »
P2Y1 Receptors Expressed by C1 Neurons Determine Peripheral Chemoreceptor Modulation of Breathing, Sympathetic Activity, and Blood Pressure.
I. C. Wenker, C. R. Sobrinho, A. C. Takakura, D. K. Mulkey, and T. S. Moreira (2013)
Hypertension 62, 263-273
   Abstract »    Full Text »    PDF »
pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract.
R. Huda, D. R. McCrimmon, and M. Martina (2013)
J Neurophysiol 110, 368-377
   Abstract »    Full Text »    PDF »
Detection of endogenous substances with enzymatic microelectrode biosensors in the kidney.
O. Palygin and A. Staruschenko (2013)
Am J Physiol Regulatory Integrative Comp Physiol 305, R89-R91
   Abstract »    Full Text »    PDF »
Real-time electrochemical detection of ATP and H2O2 release in freshly isolated kidneys.
O. Palygin, V. Levchenko, D. V. Ilatovskaya, T. S. Pavlov, R. P. Ryan, A. W. Cowley Jr., and A. Staruschenko (2013)
Am J Physiol Renal Physiol 305, F134-F141
   Abstract »    Full Text »    PDF »
Genetically Encoded Calcium Indicators and Astrocyte Calcium Microdomains.
X. Tong, E. Shigetomi, L. L. Looger, and B. S. Khakh (2013)
Neuroscientist 19, 274-291
   Abstract »    Full Text »    PDF »
Phox2b-Expressing Retrotrapezoid Neurons Are Intrinsically Responsive to H+ and CO2.
S. Wang, Y. Shi, S. Shu, P. G. Guyenet, and D. A. Bayliss (2013)
J. Neurosci. 33, 7756-7761
   Abstract »    Full Text »    PDF »
Optogenetics at a crossroads?.
S. Kasparov and S. Herlitze (2013)
Exp Physiol 98, 971-972
   Full Text »    PDF »
Cardiac optogenetics.
E. Entcheva (2013)
Am J Physiol Heart Circ Physiol 304, H1179-H1191
   Abstract »    Full Text »    PDF »
Differential Sensitivity of Brainstem versus Cortical Astrocytes to Changes in pH Reveals Functional Regional Specialization of Astroglia.
V. Kasymov, O. Larina, C. Castaldo, N. Marina, M. Patrushev, S. Kasparov, and A. V. Gourine (2013)
J. Neurosci. 33, 435-441
   Abstract »    Full Text »    PDF »
Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation.
T. Sasaki, K. Beppu, K. F. Tanaka, Y. Fukazawa, R. Shigemoto, and K. Matsui (2012)
PNAS 109, 20720-20725
   Abstract »    Full Text »    PDF »
Structural Remodeling of Astrocytes in the Injured CNS.
D. Sun and T. C. Jakobs (2012)
Neuroscientist 18, 567-588
   Abstract »    Full Text »    PDF »
General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex.
A. S. Thrane, V. Rangroo Thrane, D. Zeppenfeld, N. Lou, Q. Xu, E. A. Nagelhus, and M. Nedergaard (2012)
PNAS 109, 18974-18979
   Abstract »    Full Text »    PDF »
Purinergic Signaling in the Airways.
G. Burnstock, I. Brouns, D. Adriaensen, and J.-P. Timmermans (2012)
Pharmacol. Rev. 64, 834-868
   Abstract »    Full Text »    PDF »
Preinspiratory calcium rise in putative pre-Botzinger complex astrocytes.
Y. Okada, T. Sasaki, Y. Oku, N. Takahashi, M. Seki, S. Ujita, K. F. Tanaka, N. Matsuki, and Y. Ikegaya (2012)
J. Physiol. 590, 4933-4944
   Abstract »    Full Text »    PDF »
Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala.
J. Stehberg, R. Moraga-Amaro, C. Salazar, A. Becerra, C. Echeverria, J. A. Orellana, G. Bultynck, R. Ponsaerts, L. Leybaert, F. Simon, et al. (2012)
FASEB J 26, 3649-3657
   Abstract »    Full Text »    PDF »
Intercellular Ca2+ Waves: Mechanisms and Function.
L. Leybaert and M. J. Sanderson (2012)
Physiol Rev 92, 1359-1392
   Abstract »    Full Text »    PDF »
How does CO2 activate the neurons of the retrotrapezoid nucleus?.
P. Guyenet (2012)
J. Physiol. 590, 2183-2184
   Full Text »    PDF »
Astrocytes and disease: a neurodevelopmental perspective.
A. V. Molofsky, R. Krenick, E. Ullian, H.-h. Tsai, B. Deneen, W. D. Richardson, B. A. Barres, and D. H. Rowitch (2012)
Genes & Dev. 26, 891-907
   Abstract »    Full Text »    PDF »
Regulation of ventral surface CO2/H+-sensitive neurons by purinergic signalling.
I. C. Wenker, C. R. Sobrinho, A. C. Takakura, T. S. Moreira, and D. K. Mulkey (2012)
J. Physiol. 590, 2137-2150
   Abstract »    Full Text »    PDF »
Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity.
D. Lovatt, Q. Xu, W. Liu, T. Takano, N. A. Smith, J. Schnermann, K. Tieu, and M. Nedergaard (2012)
PNAS 109, 6265-6270
   Abstract »    Full Text »    PDF »
Glial-derived adenosine modulates spinal motor networks in mice.
E. C. Witts, K. M. Panetta, and G. B. Miles (2012)
J Neurophysiol 107, 1925-1934
   Abstract »    Full Text »    PDF »
Postsynaptic mechanisms of CO2 responses in parafacial respiratory neurons of newborn rats.
H. Onimaru, K. Ikeda, and K. Kawakami (2012)
J. Physiol. 590, 1615-1624
   Abstract »    Full Text »    PDF »
Temperature-dependent release of ATP from human erythrocytes: mechanism for the control of local tissue perfusion.
K. K. Kalsi and J. Gonzalez-Alonso (2012)
Exp Physiol 97, 419-432
   Abstract »    Full Text »    PDF »
Nucleus of Tractus Solitarius Astrocytes as Homeostatic Integrators.
C. M. Lamy (2012)
J. Neurosci. 32, 2579-2581
   Full Text »    PDF »
Optogenetic activation of LiGluR-expressing astrocytes evokes anion channel-mediated glutamate release.
D. Li, K. Herault, E. Y. Isacoff, M. Oheim, and N. Ropert (2012)
J. Physiol. 590, 855-873
   Abstract »    Full Text »    PDF »
Depletion of Extracellular Ca2+ Prompts Astroglia to Moderate Synaptic Network Activity.
D. A. Rusakov (2012)
Science Signaling 5, pe4
   Abstract »    Full Text »    PDF »
Central chemoreceptor modulation of breathing via multipath tuning in medullary ventrolateral respiratory column circuits.
M. M. Ott, S. C. Nuding, L. S. Segers, R. O'Connor, K. F. Morris, and B. G. Lindsey (2012)
J Neurophysiol 107, 603-617
   Abstract »    Full Text »    PDF »
Specific neural substrate linking respiration to locomotion.
J.-F. Gariepy, K. Missaghi, S. Chevallier, S. Chartre, M. Robert, F. Auclair, J. P. Lund, and R. Dubuc (2012)
PNAS 109, E84-E92
   Abstract »    Full Text »    PDF »
Knockout of glial channel ACD-1 exacerbates sensory deficits in a C. elegans mutant by regulating calcium levels of sensory neurons.
Y. Wang, G. D'Urso, and L. Bianchi (2012)
J Neurophysiol 107, 148-158
   Abstract »    Full Text »    PDF »
Redefining the components of central CO2 chemosensitivity - towards a better understanding of mechanism.
R. T. R. Huckstepp and N. Dale (2011)
J. Physiol. 589, 5561-5579
   Abstract »    Full Text »    PDF »
Phox2b-Expressing Neurons of the Parafacial Region Regulate Breathing Rate, Inspiration, and Expiration in Conscious Rats.
S. B. G. Abbott, R. L. Stornetta, M. B. Coates, and P. G. Guyenet (2011)
J. Neurosci. 31, 16410-16422
   Abstract »    Full Text »    PDF »
Contribution of excitatory amino acid receptors of the retrotrapezoid nucleus to the sympathetic chemoreflex in rats.
A. C. Takakura and T. S. Moreira (2011)
Exp Physiol 96, 989-999
   Abstract »    Full Text »    PDF »
Prostaglandin E2 release from astrocytes triggers gonadotropin-releasing hormone (GnRH) neuron firing via EP2 receptor activation.
J. Clasadonte, P. Poulain, N. K. Hanchate, G. Corfas, S. R. Ojeda, and V. Prevot (2011)
PNAS 108, 16104-16109
   Abstract »    Full Text »    PDF »
Purinergic modulation of preBotzinger complex inspiratory rhythm in rodents: the interaction between ATP and adenosine.
J. D. Zwicker, V. Rajani, L. B. Hahn, and G. D. Funk (2011)
J. Physiol. 589, 4583-4600
   Abstract »    Full Text »    PDF »
Breathing without CO2 Chemosensitivity in Conditional Phox2b Mutants.
N. Ramanantsoa, M.-R. Hirsch, M. Thoby-Brisson, V. Dubreuil, J. Bouvier, P.-L. Ruffault, B. Matrot, G. Fortin, J.-F. Brunet, J. Gallego, et al. (2011)
J. Neurosci. 31, 12880-12888
   Abstract »    Full Text »    PDF »
Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata.
N. Marina, A. P. L. Abdala, A. Korsak, A. E. Simms, A. M. Allen, J. F. R. Paton, and A. V. Gourine (2011)
Cardiovasc Res 91, 703-710
   Abstract »    Full Text »    PDF »
Structural plasticity of perisynaptic astrocyte processes involves ezrin and metabotropic glutamate receptors.
M. Lavialle, G. Aumann, E. Anlauf, F. Prols, M. Arpin, and A. Derouiche (2011)
PNAS 108, 12915-12919
   Abstract »    Full Text »    PDF »
Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition.
R. S. Ray, A. E. Corcoran, R. D. Brust, J. C. Kim, G. B. Richerson, E. Nattie, and S. M. Dymecki (2011)
Science 333, 637-642
   Abstract »    Full Text »    PDF »
Calcium Triggers Exocytosis from Two Types of Organelles in a Single Astrocyte.
T. Liu, L. Sun, Y. Xiong, S. Shang, N. Guo, S. Teng, Y. Wang, B. Liu, C. Wang, L. Wang, et al. (2011)
J. Neurosci. 31, 10593-10601
   Abstract »    Full Text »    PDF »
Astrocytes Display Complex and Localized Calcium Responses to Single-Neuron Stimulation in the Hippocampus.
Y. Bernardinelli, C. Salmon, E. V. Jones, W. T. Farmer, D. Stellwagen, and K. K. Murai (2011)
J. Neurosci. 31, 8905-8919
   Abstract »    Full Text »    PDF »
Involvement of TRP channels in the CO2 chemosensitivity of locus coeruleus neurons.
N. Cui, X. Zhang, J. S. Tadepalli, L. Yu, H. Gai, J. Petit, R. T. Pamulapati, X. Jin, and C. Jiang (2011)
J Neurophysiol 105, 2791-2801
   Abstract »    Full Text »    PDF »
Ventrolateral medullary functional connectivity and the respiratory and central chemoreceptor-evoked modulation of retrotrapezoid-parafacial neurons.
M. M. Ott, S. C. Nuding, L. S. Segers, B. G. Lindsey, and K. F. Morris (2011)
J Neurophysiol 105, 2960-2975
   Abstract »    Full Text »    PDF »
Remote Control of Neuronal Signaling.
S. C. Rogan and B. L. Roth (2011)
Pharmacol. Rev. 63, 291-315
   Abstract »    Full Text »    PDF »
Respiratory responses to hypercapnia and hypoxia in mice with genetic ablation of Kir5.1 (Kcnj16).
S. Trapp, S. J. Tucker, and A. V. Gourine (2011)
Exp Physiol 96, 451-459
   Abstract »    Full Text »    PDF »
Astrocytes as brain interoceptors.
A. V. Gourine and S. Kasparov (2011)
Exp Physiol 96, 411-416
   Abstract »    Full Text »    PDF »
Astrocyte chemoreceptors: mechanisms of H+ sensing by astrocytes in the retrotrapezoid nucleus and their possible contribution to respiratory drive.
D. K. Mulkey and I. C. Wenker (2011)
Exp Physiol 96, 400-406
   Abstract »    Full Text »    PDF »
Regulation of visceral sympathetic tone by A5 noradrenergic neurons in rodents.
R. Kanbar, S. D. Depuy, G. H. West, R. L. Stornetta, and P. G. Guyenet (2011)
J. Physiol. 589, 903-917
   Abstract »    Full Text »    PDF »
Control of Breathing by Raphe Obscurus Serotonergic Neurons in Mice.
S. D. DePuy, R. Kanbar, M. B. Coates, R. L. Stornetta, and P. G. Guyenet (2011)
J. Neurosci. 31, 1981-1990
   Abstract »    Full Text »    PDF »
Low Extracellular pH Induces Damage in the Pancreatic Acinar Cell by Enhancing Calcium Signaling.
A. M. Reed, S. Z. Husain, E. Thrower, M. Alexandre, A. Shah, F. S. Gorelick, and M. H. Nathanson (2011)
J. Biol. Chem. 286, 1919-1926
   Abstract »    Full Text »    PDF »
Genetic Inactivation of Kcnj16 Identifies Kir5.1 as an Important Determinant of Neuronal PCO2/pH Sensitivity.
M. C. D'Adamo, L. Shang, P. Imbrici, S. D. M. Brown, M. Pessia, and S. J. Tucker (2011)
J. Biol. Chem. 286, 192-198
   Abstract »    Full Text »    PDF »
Julius H. Comroe, Jr., Distinguished Lecture: Central chemoreception: then ... and now.
E. Nattie (2011)
J Appl Physiol 110, 1-8
   Abstract »    Full Text »    PDF »
Optogenetic experimentation on astrocytes.
M. Figueiredo, S. Lane, F. Tang, B. H. Liu, J. Hewinson, N. Marina, V. Kasymov, E. A. Souslova, D. M. Chudakov, A. V. Gourine, et al. (2011)
Exp Physiol 96, 40-50
   Abstract »    Full Text »    PDF »
Astrocytes in the Retrotrapezoid Nucleus Sense H+ by Inhibition of a Kir4.1-Kir5.1-Like Current and May Contribute to Chemoreception by a Purinergic Mechanism.
I. C. Wenker, O. Kreneisz, A. Nishiyama, and D. K. Mulkey (2010)
J Neurophysiol 104, 3042-3052
   Abstract »    Full Text »    PDF »
The 'connexin' between astrocytes, ATP and central respiratory chemoreception.
G. D. Funk (2010)
J. Physiol. 588, 4335-4337
   Full Text »    PDF »
Control of Breathing by "Nerve Glue".
K. Ballanyi, B. Panaitescu, and A. Ruangkittisakul (2010)
Science Signaling 3, pe41
   Abstract »    Full Text »    PDF »
Developmental Origin of PreBotzinger Complex Respiratory Neurons.
P. A. Gray, J. A. Hayes, G. Y. Ling, I. Llona, S. Tupal, M. C. D. Picardo, S. E. Ross, T. Hirata, J. G. Corbin, J. Eugenin, et al. (2010)
J. Neurosci. 30, 14883-14895
   Abstract »    Full Text »    PDF »
Connexin hemichannel-mediated CO2-dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity.
R. T. R. Huckstepp, R. id Bihi, R. Eason, K. M. Spyer, N. Dicke, K. Willecke, N. Marina, A. V. Gourine, and N. Dale (2010)
J. Physiol. 588, 3901-3920
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882