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The Journal of Neuroscience, January 31, 2007, 27(5):993-1005; doi:10.1523/JNEUROSCI.3948-06.2007

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Behavioral/Systems/Cognitive
P2Y₁ Receptor Modulation of the Pre-Bötzinger Complex Inspiratory Rhythm Generating Network In Vitro

Amanda R. Lorier,^1,2 Adrianne G. Huxtable,¹ Dean M. Robinson,² Janusz Lipski,² Gary D. Housley,² and Gregory D. Funk^1,2

¹Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7, and ²Department of Physiology, Faculty of Medicine and Health Sciences, University of Auckland, Auckland, Private Bag 92019, New Zealand

Correspondence should be addressed to Dr. Gregory D. Funk, 7-50 Medical Sciences Building, Department of Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. Email: gf{at}ualberta.ca

ATP is released during hypoxia from the ventrolateral medulla (VLM) and activates purinergic P2 receptors (P2Rs) at unknown loci to offset the secondary hypoxic depression of breathing. In this study, we used rhythmically active medullary slices from neonatal rat to map, in relation to anatomical and molecular markers of the pre-Bötzinger complex (preBötC) (a proposed site of rhythm generation), the effects of ATP on respiratory rhythm and identify the P2R subtypes responsible for these actions. Unilateral microinjections of ATP in a three-dimensional grid within the VLM revealed a "hotspot" where ATP (0.1 mM) evoked a rapid 2.2 ± 0.1-fold increase in inspiratory frequency followed by a brief reduction to 0.83 ± 0.02 of baseline. The hotspot was identified as the preBötC based on histology, overlap of injection sites with NK1R immunolabeling, and potentiation or inhibition of respiratory frequency by SP ([Sar⁹-Met(O₂)¹¹]-substance P) or DAMGO ([D-Ala²,N-MePhe⁴,Gly-ol⁵]-enkephalin), respectively. The relative potency of P2R agonists [2MeSADP (2-methylthioadenosine 5'-diphosphate) 2MeSATP (2-methylthioadenosine 5'-triphosphate) ATPs (adenosine 5'-[-thio]triphosphate tetralithium salt) ATP >> UTP ßmeATP (,ß-methylene-adenosine 5'-triphosphate)] and attenuation of the ATP response by MRS2179 (2'-deoxy-N⁶-methyladenosine-3',5'-bisphosphate) (P2Y₁ antagonist) indicate that the excitation is mediated by P2Y₁Rs. The post-ATP inhibition, which was never observed in response to ATPs, is dependent on ATP hydrolysis. These data establish in neonatal rats that respiratory rhythm generating networks in the preBötC are exquisitely sensitive to P2Y₁R activation, and suggest a role for P2Y₁Rs in respiratory motor control, particularly in the P2R excitation of rhythm that occurs during hypoxia.

Key words: purine receptor; neonatal rat; ATP; adenosine; substance P; immunohistochemistry

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Received June 21, 2006; revised Nov. 21, 2006; accepted Dec. 13, 2006.

Correspondence should be addressed to Dr. Gregory D. Funk, 7-50 Medical Sciences Building, Department of Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. Email: gf{at}ualberta.ca

This article has been cited by other articles:

				M. F. Ireland, F. C. Lenal, A. R. Lorier, D. E. Loomes, T. Adachi, T. S. Alvares, J. J. Greer, and G. D. Funk Distinct receptors underlie glutamatergic signalling in inspiratory rhythm-generating networks and motor output pathways in neonatal rat J. Physiol., May 1, 2008; 586(9): 2357 - 2370. [Abstract] [Full Text] [PDF]

				A. R. Lorier, J. Lipski, G. D. Housley, J. J. Greer, and G. D. Funk ATP sensitivity of preBotzinger complex neurones in neonatal rat in vitro: mechanism underlying a P2 receptor-mediated increase in inspiratory frequency J. Physiol., March 1, 2008; 586(5): 1429 - 1446. [Abstract] [Full Text] [PDF]

				E. A. Crowder, M. S. Saha, R. W. Pace, H. Zhang, G. D. Prestwich, and C. A. Del Negro Phosphatidylinositol 4,5-bisphosphate regulates inspiratory burst activity in the neonatal mouse preBotzinger complex J. Physiol., August 1, 2007; 582(3): 1047 - 1058. [Abstract] [Full Text] [PDF]

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