Spinal adenosine A2a receptor activation elicits long-lasting phrenic motor facilitation.
Acute intermittent hypoxia elicits a form of spinal, brain-derived neurotrophic factor (BDNF)-dependent respiratory plasticity known as phrenic long-term facilitation. Ligands that activate G(s)-protein-coupled receptors, such as the adenosine 2a receptor, mimic the effects of neurotrophins in vitro by transactivating their high-affinity receptor tyrosine kinases, the Trk receptors. Thus, we hypothesized that A2a receptor agonists would elicit phrenic long-term facilitation by mimicking the effects of BDNF on TrkB receptors. Here we demonstrate that spinal A2a receptor agonists transactivate TrkB receptors in the rat cervical spinal cord near phrenic motoneurons, thus inducing long-lasting (hours) phrenic motor facilitation. A2a receptor activation increased phosphorylation and new synthesis of an immature TrkB protein, induced TrkB signaling through Akt, and strengthened synaptic pathways to phrenic motoneurons. RNA interference targeting TrkB mRNA demonstrated that new TrkB protein synthesis is necessary for A2a-induced phrenic motor facilitation. A2a receptor activation also increased breathing in unanesthetized rats, and improved breathing in rats with cervical spinal injuries. Thus, small, highly permeable drugs (such as adenosine receptor agonists) that transactivate TrkB receptors may provide an effective therapeutic strategy in the treatment of patients with ventilatory control disorders, such as obstructive sleep apnea, or respiratory insufficiency after spinal injury or during neurodegenerative diseases.
Golder
Francis J
FJ
Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
Ranganathan
Lavanya
L
Satriotomo
Irawan
I
Hoffman
Michael
M
Lovett-Barr
Mary Rachael
MR
Watters
Jyoti J
JJ
Baker-Herman
Tracy L
TL
Mitchell
Gordon S
GS
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology*; D010991:Plethysmography / Q000379:methods; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000503:physiopathology; D014970:Xanthines / Q000494:pharmacology
D058917:Adenosine A2 Receptor Antagonists; D000959:Antihypertensive Agents; D019208:Brain-Derived Neurotrophic Factor; C113602:MSX 3 compound; D010627:Phenethylamines; D034741:RNA, Small Interfering; D043705:Receptor, Adenosine A2A; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D020813:Receptor, trkB; D000241:Adenosine