Protein kinase A inhibition in vivo depresses respiratory drive but not rhythm in central respiratory networks of adult rat

      Little is known about signal transduction cascades that shape the excitability of respiratory neurons in vivo to regulate respiratory rhythm and pattern. Here we determined the respiratory effects of blocking the cAMP-protein kinase A (PKA) pathway in subnuclei of the ventral respiratory column and spinal cord. Microinjection of Rp-adenosine 3′,5′-cyclic monophosphothioate (Rp-cAMPS; 0.5, 1, 5 and 15 nMol in 50 nl), a PKA inhibitor, were made into glutamate identified sites of urethane-anaesthetised (1.3 g/kg ip), paralysed, vagotomised and artificially ventilated adult Sprague Dawley rats (n=30). Phrenic and splanchnic sympathetic nerves, end tidal CO2 and arterial pressure were recorded. Bilateral microinjection of 5 nMol Rp-cAMPS into the preBötzinger Complex (preBötC, n=5) caused a robust depression of phrenic burst amplitude (22±6%) and an increase in phrenic burst frequency (126±6%). Pretreatment with strychnine (n=4), but not bicuculline (n=4) blocked the Rp-cAMPS-evoked increase in frequency, but not the depression of phrenic amplitude. Microinjection of Rp-cAMPS in the rostral ventral respiratory group (rVRG, n=4) also significantly depressed phrenic drive, but had little effect on phrenic burst frequency. Rp-cAMPS injections into the Bötzinger Complex caused a modest, transient reduction in phrenic frequency; Rp-cAMPS injections into the phrenic motonucleus had no effect on phrenic nerve activity. These findings demonstrate tonically active post-synaptic cAMP-PKA signaling in the preBötC and rVRG, but not phrenic motonucleus, is crucial for maintenance of basal respiratory drive. Furthermore, cAMP-PKA signaling in the preBötC does not underpin rhythmogenesis, but does regulate the release of glycine onto preBötC neurons.
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