Divergent cAMP signaling differentially regulates serotonin-induced spinal motor plasticity.
Spinal metabotropic serotonin receptors encode transient experiences into long-lasting changes in motor behavior (i.e. motor plasticity). While interactions between serotonin receptor subtypes are known to regulate plasticity, the significance of molecular divergence in downstream G protein coupled receptor signaling is not well understood. Here we tested the hypothesis that distinct cAMP dependent signaling pathways differentially regulate serotonin-induced phrenic motor facilitation (pMF); a well-studied model of spinal motor plasticity. Specifically, we studied the capacity of cAMP-dependent protein kinase A (PKA) and exchange protein activated by cAMP (EPAC) to regulate 5-HT2A receptor-induced pMF within adult male rats. Although spinal PKA, EPAC and 5-HT2A each elicit pMF when activated alone, concurrent PKA and 5-HT2A activation interact via mutual inhibition thereby blocking pMF expression. Conversely, concurrent EPAC and 5-HT2A activation enhance pMF expression reflecting additive contributions from both mechanisms. Thus, we demonstrate that distinct downstream cAMP signaling pathways enable differential regulation of 5-HT2A-induced pMF. Conditional activation of independent signaling mechanisms may explain experience amendable changes in plasticity expression (i.e. metaplasticity), an emerging concept thought to enable flexible motor control within the adult central nervous system.
Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA.
D P
DP
Fields
Department of Physical Therapy and McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA. Electronic address: gsmitche@phhp.ufl.edu.
G S
GS
Mitchell
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage; D015398:Signal Transduction
D020662:Guanine Nucleotide Exchange Factors; C526973:Rapgef3 protein, rat; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D012701:Serotonin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
5-HT2 receptor; 5-HT7 receptor; EPAC; Exchange protein activated by cAMP; Motor neuron; PKA; Phrenic; Protein kinase A; Respiratory plasticity; Spinal cord
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