cAMP-dependent protein kinase inhibits 7 nicotinic receptor activity in layer1 cortical interneurons through activation of D1/D5 dopamine receptors

摘要

Phosphorylation of ion channels, including nicotinic acetylcholine receptors (nAChRs), by protein kinases plays a key role in the modification of synaptic transmission and neuronal excitability. 7 nAChRs are the second most prevalent nAChR subtype in the CNS following 42. Serine 365 in the M3-M4 cytoplasmic loop of the 7 nAChR is a phosphorylation site for protein kinase A (PKA). D1/D5 dopamine receptors signal through the adenylate cyclase-PKA pathway and play a key role in working memory and attention in the prefrontal cortex. Thus, we examined whether the dopaminergic system, mediated through PKA, functionally interacts with the 7-dependent cholinergic neurotransmission. In layer1 interneurons of mouse prefrontal cortex, 7 nicotinic currents were decreased upon stimulation with 8-Br-cAMP, a PKA activator. In HEK 293T cells, dominant negative PKA abolished 8-Br-cAMP's effect of diminishing 7 nicotinic currents, while a constitutively active PKA catalytic subunit decreased 7 currents. In brain slices, the PKA inhibitor KT-5720 nullified 8-Br-cAMP's effect of attenuating 7 nicotinic responses, while applying a PKA catalytic subunit in the pipette solution decreased 7 currents. 8-Br-cAMP stimulation reduced surface expression of 7 nAChRs, but there was no change in single-channel conductance. The D1/D5 dopamine receptor agonist SKF83822 similarly attenuated 7 nicotinic currents from layer1 interneurons and this attenuation of nicotinic current was prevented by KT-5720. These results demonstrate that dopamine receptor-mediated activation of PKA negatively modulates nicotinic neurotransmission in prefrontal cortical interneurons, which may be a contributing mechanism of dopamine modulation of cognitive behaviours such as attention or working memory.